Bhat et al. Molecular Cancer (2020) 19:57 https://doi.org/10.1186/s12943-020-01175-9

REVIEW Open Access Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance Ajaz A. Bhat1, Salma N. Younes2,3, Syed Shadab Raza4, Lubna Zarif2,3, Sabah Nisar1, Ikhlak Ahmed1, Rashid Mir5, Sachin Kumar6, Surender K. Sharawat6, Sheema Hashem1, Imadeldin Elfaki7, Michal Kulinski3, Shilpa Kuttikrishnan3, Kirti S. Prabhu3, Abdul Q. Khan3, Santosh K. Yadav1, Wael El-Rifai8, Mohammad A. Zargar9, Hatem Zayed2, Mohammad Haris1,10* and Shahab Uddin3*

Abstract Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate. Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets. Keywords: Cancer, Circular RNAs, Chromatin, Drug resistance, Epigenetics, Gene regulation, Long non-coding RNAs, MicroRNAs, Metastasis, Signaling pathways

Introduction symptoms, including thrombocytopenia, anemia, and im- Leukemia is a class of blood cancers characterized by an munodeficiency. Hematological cancers are ranked as the oligoclonal expansion of hematopoietic cells that infiltrate 11th common type of cancer and the 10th common cause the bone marrow and can also invade the blood and other of cancer-related death. More than 350,000 new leukemia extramedullary tissues [1]. The proliferation of leukemic cases and 265,000 leukemia deaths were estimated to have cells causes the expulsion of the normal hematopoietic occurred in 2012 [2]. In the United States, leukemia ac- cells and the loss of their functions, leading to severe counts for approximately 4% of cancer-derived mortalities and 3.5% of all cancer cases. The incidence, mortality, and

* Correspondence: [email protected]; [email protected]; survival of leukemia depends on the diagnosis, prognosis, [email protected] as well as natural history of neoplasms arising from the 1Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar malignant transformation of hemopoietic stem cells or 3Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar progenitor cells in the bone marrow [3]. Full list of author information is available at the end of the article

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Leukemia can be classified according to its progression prospects for treatment, diagnosis, and prognostication pattern (acute or chronic) and affected lineage (lymph- of different types of leukemia. oid or myeloid). The four major subtypes are acute lymphoblastic leukemia (ALL), chronic lymphoblastic Non-coding RNA networks and leukemia leukemia (CLL), acute myeloid leukemia (AML), and Currently, there is an overpowering proof showing that chronic myeloid leukemia (CML) [4, 5]. ALL is one of transcriptional, posttranscriptional and translational the most common types of malignancy in children controls, mediated by different non-coding RNAs, apply worldwide [6], while the other subtypes are more com- necessary pleiotropic activities on various highlights of mon in adults. In all types of leukemia, the abnormal leukemia science. This has opened space for disclosure proliferation of bone marrow and blood cells interferes and portrayal of non-coding RNAs as biomarkers in with the production of functionally healthy cells. Thus, leukemia and prompted several investigations in this anemia ensues in people with leukemia resulting in re- field over the last 10 years. The full picture of these un- duced ability to fight infections and clotting disorders. usually communicating non-coding RNAs in leukemia is For most patients, the causes of leukemia and its sub- slowly developing [9–17]. The vital role and underlying types are unclear partly due to diverse abnormalities and molecular mechanisms of non-coding RNAs and their multiple risk factors. However, the genetic background therapeutic potential in leukemia are outlined in interacting with environmental factors including expos- Table 1. ure to high doses of radiation or carcinogenic agents, such as benzene; parental occupational exposures; and Characteristics of non-coding RNA networks infections all contribute to a higher risk of developing Latest proceedings in high-throughput sequencing for leukemia [7]. whole genomes and transcriptomes demonstrated that The underlying molecular mechanisms mediating the fewer than 2% of the entire human genome encodes pro- pathophysiology of leukemia are not fully understood. teins, whereas a large portion of the human genome, Thus, deeper insights in the genetic basis of the disease constituting at least 75%, encodes ncRNAs [74]. Cur- and their influence on the progress of the disease and rently, ncRNAs are classified according to transcript size treatment response are crucial to discovering new prog- into two broad categories, small (< 200 nucleotides; nostic markers and novel therapeutic targets that can ncRNAs) and long (> 200 nucleotides; lncRNAs) non- open new doors in personalizing treatment. The focus of coding RNAs (lncRNAs) (Fig. 1). The ncRNAs play a research for decades has been on the expression of mes- major role in the process of gene expression, RNA mat- senger RNAs that code for proteins. Recently, there has uration, and protein synthesis [75–77]. With the emer- been much research suggesting that protein-coding ging evidence, it has become quite evident that not only genes only cover a small proportion of the human tran- protein-coding mutations but variations within the non- scriptome and that a more significant proportion of the coding genome are also responsible for various cancer human transcriptome (66%) is composed of long non- etiologies [78, 79]. coding RNAs (long ncRNAs), antisense and micro RNAs (miRNAs), and pseudogenes [8]. Current evidence has Long non-coding RNAs shown that ncRNAs might act as a link between the gen- lncRNAs are defined as transcripts with lengths exceed- ome and the environment by being an intricate player in ing 200 nucleotides that are not translated into protein the process of gene expression, contributing to the [80, 81], and most of them are markedly expressed in pathogenesis of various human diseases, including can- differentiated tissues or particular cancer types [78]. cer. Several studies have documented the involvement of RNA polymerase II is responsible for executing the tran- ncRNAs in differentiation, proliferation, and apoptosis of scription of lncRNAs, and generally, they are expressed leukemic cells and their potential as a future prognostic in a tissue-specific manner [78, 82]. LncRNAs regulate biomarker. several biological processes such as differentiation, de- In the current review, we discussed the characteristics velopment and biogenesis and multiple human disor- and role of leukemia related non-coding RNAs. We pro- ders, including certain malignancies are associated with vided a succinct overview of the current understanding deregulation of lncRNAs. Deregulation of lncRNAs was of non-coding RNA expression patterns in different demonstrated to be intrinsically connected with human types of leukemia, the mechanisms that contribute to illnesses, including different kinds of malignant growths leukemia carcinogenesis, and their role in drug resist- [78, 82]. Because of this, lncRNAs have become a focal ance. Deciphering the essential role of diverse non- point of researchers, and practical explanations of the coding RNAs may improvise the understanding of the roles of lncRNAs are an evolving line of research. Usu- underlying biological events, ultimately leading to the ally, lncRNAs utilize various instruments to implement identification of novel therapeutic targets, opening new their functions at a cellular level. For example, lncRNAs Bhat et al. Molecular Cancer (2020) 19:57 Page 3 of 21

Table 1 Roles of ncRNAs implicated in leukemia Type of ncRNA ncRNA Type of leukemia Expression in leukemia Mechanism/target/pathway References miRNA miR-194-5p AML Upregulated inducing BCLAF1; BCL2-associated [18] transcription factor 1 (BCLAF1) miRNA miR-103 AML Upregulated Blocking PI3K/AKT signal pathway by [19] regulation of COP1 miRNA miR-15a CML-CP Upregulated Expression modulated by BCR–ABL is linked [20] to CML progression and imatinib resistance miRNA miR-130b CML-CP Downregulated Expression modulated by BCR–ABL is linked [20] to CML progression and imatinib resistance miRNA miR-145 CML-CP Upregulated Expression modulated by BCR–ABL is linked [20] to CML progression and imatinib resistance miRNA miR-16 CML-CP Downregulated Expression modulated by BCR–ABL is linked [20] to CML progression and imatinib resistance miRNA miR-26a CML-CP Downregulated Expression modulated by BCR–ABL is linked [20] to CML progression and imatinib resistance miRNA miR-146a CML-CP Downregulated Expression modulated by BCR–ABL is linked [20] to CML progression and imatinib resistance miRNA miR-29c CML-CP Downregulated Expression modulated by BCR–ABL is linked [20] to CML progression and imatinib resistance miRNA miR-96 AML Downregulated Oncogene Metastasis-associated lung [21] adenocarcinoma transcript 1 (MALAT1) knockdown inhibited proliferation, promoted apoptosis and enhanced Ara-C sensitivity in AML cells by upregulating miR-96 miRNA miR-128b ALL Downregulated downregulation of the MLL-AF4 chimeric [22] fusion proteins MLL-AF4 and AF4-MLL that are generated by chromosomal translocation t(4;11) miRNA miR-34a AML Downregulated TUG1 confers Adriamycin resistance in [23, 24] acute myeloid leukemia by epigenetically suppressing miR-34a expression via EZH2 miRNA miR-451a CML Downregulated NR [25] miRNA let-7b-5p CML Downregulated NR [25] miRNA hsa-miR-425 AML Upregulated Through calcium signaling pathway and [26] natural killer cell mediated cytotoxicity. miRNA hsa-miR- 200c AML Downregulated NR [26, 27] miRNA hsa-mir-30a CML Downregulated NR [28] miRNA miRNA-155 ALL Upregulated NR [29] miRNA miR-130a CML Downregulated Functions as a tumor suppressor by [30] inhibiting multiple anti-apoptosis proteins, including BCL-2, MCL-1 and XIAP. miRNA miR-125b AML; ALL Upregulated microRNA125b promotes leukemia cell [31] resistance to daunorubicin through inhibiting apoptosis miRNA miR-224 CML Downregulated miR-224, along with let-7i, regulate the [32] proliferation and chemosensitivity of CML cells probably via targeting ST3GAL IV. lncRNA HOXA-AS2 AML Upregulated HOXA-AS2 negatively regulates the [33] expression of miR-520c-3p in ADR cells. S100A4 was predicted as a downstream target of miR-520c-3p, lncRNA TUG1 AML Upregulated TUG1 confers Adriamycin resistance in [23, 34] acute myeloid leukemia by epigenetically suppressing miR-34a expression via EZH2 lncRNA RP11-342 M1.7 AML Upregulated Involved in neoplastic signaling pathways [35] Bhat et al. Molecular Cancer (2020) 19:57 Page 4 of 21

Table 1 Roles of ncRNAs implicated in leukemia (Continued) Type of ncRNA ncRNA Type of leukemia Expression in leukemia Mechanism/target/pathway References lncRNA CDCA4P3 AML Upregulated Involved in neoplastic signaling pathways [35] lncRNA CES1P1 AML Downregulated Involved in neoplastic signaling pathways [35] lncRNA AC008753.6 AML Downregulated Involved in neoplastic signaling pathways [35] lncRNA RP11-573G6.10 AML Downregulated Involved in neoplastic signaling pathways [35] lncRNA MEG3 CML Downregulated contributes to imatinib resistance through [36] regulating miR-21 lncRNA PANDAR AML Upregulated NR [37] lncRNA GAS5 AML Upregulated Via affecting hematopoietic reconstitution [38] lncRNA UCA1 CML Upregulated UCA1acts as a ceRNA Against miR-16 in [39] Chronic Myeloid Leukemia Cells lncRNA MALAT1 CML Upregulated MALAT1 promotes imatinib resistance of [40] CML cells by targeting miR-328 lncRNA UCA1 AML Upregulated knockdown of UCA1 plays a role in [41] overcoming the chemoresistance of pediatric AML, by inhibiting glycolysis through regulating the miR-125a/HK2 pathway. lncRNA NONHSAT076891 APL Upregulated NR [42] lncRNA CRNDE AML Upregulated NR [13] lncRNA LINC00899 AML Upregulated NR [12] lncRNA HOTAIR CML Upregulated Knockdown of HOTAIR expression [43] downregulates MRP1 expression levels and reverses imatinib resistance via PI3K/Akt pathway. lncRNA IRAIN AML Downregulated Interaction with chromatin DNA and [44] involvement in the formation of an intrachromosomal promoter loop lncRNA CCDC26 AML Upregulated NR [45] lncRNA KCNQ1OT1 AML Upregulated NR [46] lncRNA NONHSAT027612.2 ALL Upregulated Through regulating immune [47] response-associated pathways. lncRNA NONHSAT134556.2 ALL Upregulated Through regulating immune [47] response-associated pathways. lncRNA LINP1 AML Upregulated Via HNF4alpha/AMPK/WNT5A [48] signaling pathway lncRNA SNHG3 AML Upregulated SNHG3 elicits a growth-promoting [49] function in AML via sponging miR-758-3p to regulate SRGN expression lncRNA LUNAR1 ALL Downregulated Proliferation of T cells [50, 51] lncRNA T-ALL-R-LncR1 ALL Upregulated Regulate apoptosis by Par-4/THAP1 [52] protein complex lncRNA HOTAIRM1 AML Upregulated Chromatin modification, myeloid [53, 54] differentiation lncRNA PVT1 AML Upregulated Oncogene, induce proliferation and [55] suppress Apoptosis lncRNA ANRIL AML/ALL Upregulated Myeloblast proliferation [56] lncRNA BGL3 CML Upregulated Apoptosis and DNA methylation [57] circRNA f-circPR AML Upregulated High proliferation, chemo resistance, [58] Differential expression circRNA circ-PVT1 AML Upregulated Involved in the development of [59] leukaemia (AML) Bhat et al. Molecular Cancer (2020) 19:57 Page 5 of 21

Table 1 Roles of ncRNAs implicated in leukemia (Continued) Type of ncRNA ncRNA Type of leukemia Expression in leukemia Mechanism/target/pathway References circRNA circNPM1 75,001 AML Upregulated NPM1/regulate myeloid differentiation [60] (hsa_circ_0075001) though miR-181, circRNA circ-HIPK2 AML Downregulated Regulate differentiation though miR-124-3p [61] circRNA circRNA-DLEU2 AML Upregulated Enhanced cell division, survival, and [62] proliferation with suppressed apoptosis through miR-496/ PRKACB circRNA hsa_circ_0004277 AML Downregulated Act as prognostic factor for survival [63] outcome in AML patients. Target multiple miRNAs and Genes miR-138-5p, miR-30c-1- 3p, miR-892b, miR-571, miR-328-3p/SH3GL2, PPARGC1A, PIP4K2C, SH2B3, ZNF275, and ATP1B4 circRNA circ-CBFB CLL Upregulated regulating miR-607/FZD3/Wnt/beta-catenin [64] pathway circRNA circ_0132266 CLL Downregulated circ_0132266 acts as a sponge of miR-337- [65] 3p and regulates its activity, resulting in a downstream change of target-gene PML, influencing cell viability. circRNA circPAN3 AML Upregulated circPAN3-miR-153-5p/miR-183-5p-XIAP axis; [66, 67] circPAN3 may facilitate AML drug resistance through regulating autophagy and influencing expression of apoptosis-related proteins circRNA circ_0009910 AML Upregulated knockdown of circ_0009910 inhibited AML [68] cell proliferation and induced apoptosis by acting as a sponge for miR-20a-5p circRNA circ_100053 CML Upregulated involved in imatinib resistance [69] circRNA hsa_circ_0080145 CML Upregulated knockdown of hsa_circ_0080145 [70] significantly suppressed CML cell proliferation thorugh acting as a sponge for miR-29b. circRNA circ-ANAPC7 AML Upregulated circ-ANAPC7 targets the MiR-181 Family [71] circRNA hsa_circ_0004277 AML Downregulated Increasing level of hsa_circ_0004277 by [63] chemotherapy was associated with successful AML treatment circRNA circBA9.3 CML Upregulated Chemoresistance, Oncogene, Induce cell [72] proliferation and supressed apoptosis siRNA SKP2 AML Upregulated SKP2 inhibits the degradation of P27kip1 [73] and down-regulates the expression of MRP can influence chromatin redesigning and methylation, example, HOTTIP and CCAT1, results in tweaking act as a miRNA restraint sponge, and regulate protein chromosome circling and influencing gene promoters complexes stability [76, 83, 84] (Fig. 2). [89, 90]. The lncRNA Firre was demonstrated to be Several pieces of evidence have shown that some crucial in maintaining inactivation of the X chromo- lncRNAs, for example, TARID, Kcnq1ot1, and some [91]. X-linked lncRNA Firre cohesion with the AS1DHRS4, engage DNA methyltransferases to alter chromatin remodelers, CTCF and attachment, is one of chromatin conformation or act to alter the position of the essential steps in the process and includes changing nucleosome through the SWI/SNF complex as observed chromatin confirmation during the inactivation of X in SChLAP1 [85–87]. The histone methyltransferase chromosome process. Subsequently, the inactive X poly-comb repressive complex-2 (PRC2) is a widely chromosome is positioned close to the nucleolus and studied protein managed by ncRNAs and has shown as maintain H3K27me3 methylation [91]. Different an intermediary target of lncRNAs [88]. PRC2 appears lncRNAs have their distinct inhibitory roles regulated to play a role in inactivating chromatin through initiat- through the action of authoritative miRNAs, which can ing the inhibitory H3K427me3 histone marks [88]. seize the biomolecules and diminish their potential to Also, chromatin alterations by specific lncRNAs, for inhibit their targets [82]. Bhat et al. Molecular Cancer (2020) 19:57 Page 6 of 21

Fig. 1 Classification of noncoding RNAs (ncRNAs). Noncoding RNAs are classified into small ncRNAs (< 200 nucleotides) or long ncRNAs (> 200 nucleotides) based on their length. Small ncRNAs are further classified into functional and regulatory noncoding RNAs while long ncRNAs are classified based on their structure, function and location

The roles of miRNA in leukemia have been broadly lymphoblastic leukemia through the HOXA3/EGFR/Ras/ explored in recent years, but the utilitarian roles of Raf/MEK/ERK pathway [33]. Likewise, exhaustive lncRNAs in such tumors are yet unclear. Numerous lncRNA expression profiling by RNA sequencing has lncRNAs are deregulated in different sorts of malignant uncovered that lncRNA RP11-342 M1.7, lncRNA growths, including head and neck cancer [92]. Unmis- CES1P1 and lncRNA AC008753.6 are both independent takable expression profiles of lncRNA have been distin- as well as in combination, serve as predictive factors for guished in leukemia [9, 33, 35, 45, 47–49, 93–99]. Some AML risk [35]. LncRNA LINP1 was found to regulate of these have been demonstrated to have well- AML progression employing the HNF4alpha/AMPK/ understood jobs in the development and progression of WNT5A signaling pathway [48]. miR-335-3p dysregula- leukemia, suggesting the vital use of lncRNAs as novel tion, directed by the lncRNAs NEAT1 and MALAT1, is biomarkers and potential targets for the treatment of associated with a poor prognosis in childhood ALL. By leukemia. Recent shreds of evidence have demonstrated and large, these discoveries provide a greater depth of that few lncRNAs play significant physiological roles and understanding into the pathogenesis of a high-risk group are essential for regulating different levels of gene ex- of leukemias that can help clinicians explore the possi- pression [84, 100, 101]. While some of the lncRNAs act bility of using lncRNAs for treatment. as oncogenes, others function as tumor suppressors, and they are involved in cellular processes, including the cell Micro RNAs cycle and tumor invasion and metastasis [102]. For ex- Micro RNAs (miRNAs) are a subset of non-coding ample, the lncRNA HOXA cluster antisense RNA2 RNAs ~ 19–20 nt in length with 5′-phosphate and 3′- (HOXA-AS2), which has been previously shown to have hydroxyl ends. The ribonuclease Dicer processes them oncogenic properties in several human malignancies, from precursors having a characteristic hairpin second- was found to diminish glucocorticoid sensitivity in acute ary structure (Fig. 3). miRNAs were first discovered in Bhat et al. Molecular Cancer (2020) 19:57 Page 7 of 21

Fig. 2 General mechanisms for functions of Long Noncoding RNAs. Nuclear lncRNAs are implicated in Epigenetic regulations, Transcriptional regulations, and splicing regulations while cytoplasmic lncRNAs are involved in mRNA stability, act as small regulatory RNA sponges, regulate mRNA translation and can also be small peptide producers

Caenorhabditis elegans and have since been found in the function of miRNA and use this information to most eukaryotes, including humans [103–105]. Accord- guide treatment. ing to the reports, human genome comprised of approxi- mately 1–5% of miRNA, which is responsible for at least Role of microRNA gene abnormalities in leukemia 30% of the protein-coding genes [106–110]. To date, Abnormal expression of miRNA has been reported in many 940 distinct miRNA molecules have been identified malignancies, including stomach [123], brain [124], breast [111–113]. The knowledge about the specific targets and [125], lung [126], liver [127], colon [128], leukemia [129] biological functions of miRNA molecules is still scarce, and lymphoma [130]. Many studies have reported that but their crucial role in the regulation of gene expres- microRNA function as a tumor suppressor or oncogene. In sion, controlling diverse cellular and metabolic pathways most of the tumors, the tumor -suppressing miRNAs are is well-evident [114–119]. As this field is still emerging, downregulated, whereas the oncogenic miRNAs are overex- there are only a limited number of studies in the context pressed. Jongen-Lavrencic et al., [131]reportedthatmiR- of miRNAs in leukemia. 155 is upregulated in hematopoietic stem cells carrying While some of the miRNAs work as oncogenes, others FLT3-ITD and nucleophosmin (NPM1) gene mutations of work as tumor suppressors [120]. For instance, it has AML patients. Similarly, Lagos-Quintana et al., [132]in been shown that the balance between miR-194-5p and murine lymphocyte precursors reported increased expres- its target BCL2-associated transcription factor 1 sion of miR-155 that induces polyclonal lymphocytosis and (BCLAF1) is commonly deregulated in AML patients develops high-grade lymphocytic leukemia. Also, in the [18]. Also, miR-10a-5p was found to be overexpressed in case of a myeloproliferative disease, the overexpression of relapsed AML cases [121]. Furthermore, the expression miR-155 was reported that leads to increased granulocyte- of miR-96 was downregulated in newly diagnosed AML monocyte cells [122]. Fuster O et al., [133] suggested that and is associated with leukemic burden [122]. Collect- abnormal expression of miR-155 signaling targets SHIP1 ively, these findings allow us to develop a better under- and CEBPB in AML patients, both of which are critical in standing of the underlying mechanisms of a high-risk granulopoiesis. Yamamoto et al., [134]reportedthatmiR- group of leukemias that can assist clinicians in clarifying 133 in leukemic cells targets the Ecotropic viral integration Bhat et al. Molecular Cancer (2020) 19:57 Page 8 of 21

Fig. 3 MicroRNA (miRNA) biogenesis and regulation of gene expression. The series of events includes the production of the primary miRNA (pri- miRNA) transcript by RNA polymerase II or III and cleavage of the pri-miRNA into a stem-loop structured miRNA precursor (pre-miRNA) by the microprocessor complex Drosha-DGCR8 (Pasha) in the nucleus. Then the pre-miRNA hairpin is exported from the nucleus by Exportin-5-Ran-GTP. In the cytoplasm, the RNase Dicer in complex with the double-stranded RNA-binding protein TRBP cleaves the pre-miRNA hairpin to its mature length. The functional strand of the mature miRNA is loaded together with Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides the RISC to silence target mRNAs through mRNA cleavage, translational repression or deadenylation, whereas the passenger strand is degraded

site 1 (Evi1) which upregulated the drug sensitivity and sug- experiments in leukemic cell lines HL60, NB4, and K562 gested that miR-133 can be a potential therapeutic target and reported that the upregulation of miR-181a induces for Evi1-overexpressing leukemia. In AML cell lines, Xiao higher cell proliferation thereby increased cell cycling by et al. [135]reportedelevatedexpressionofmiR-223that targeting ATM. It has been investigated that the transfec- inhibited proliferation and cell motility but promote cell tion of miR-128 increased the drug sensitivity, enhanced apoptosis. Several studies reported that ectopic miR-223 apoptosis in HL60 cell lines [140], whereas the DNA dam- overexpression decreased the tumorigenesis by controlling age was tolerated; however, the molecular mechanism is yet the G1/S cell cycle phase transition [136]. Lin X et al., [137] to be elucidated. However, Volinia S et al., [141]reported investigated that the miR-370 expression was decreased in that miR-128 to be overexpressedandupregulatedindiffer- pediatric AML patients which in turn contribute to the sig- ent malignancies, but its expression was decreased in AML nificant progression of the disease and it was suggested that cells carrying NPM1 mutations. Imatinib Resistance has the miR-370 expression could act as non-invasive diagnos- been reported as a major hurdle for the treatment of tic and, a prognostic marker for pediatric AML patients. chronic myeloid leukemia (CML). The miRNAs are in- Magee P et al. has reported [138] that abnormal expression volved in various processes from the development to drug of microRNAs induce chemoresistance that affects a variety resistance of tumors, including chronic myeloid leukemia of cancer types and he also determined that the forced ex- (CML). Recent data suggested that miR-221-STAT5 axis pression of miR-22 and miR-193a leads to inhibition of played crucial roles in controlling the sensitivity of CML leukemia progression. Liu X et al., [139] conducted cells to imatinib [142]. Another recent finding reports that Bhat et al. Molecular Cancer (2020) 19:57 Page 9 of 21

Fig. 4 General mechanisms for functions of circular RNAs (circRNAs). circRNAs can function as a sponge for a miRNA/RBP keeping miRNA/RBP away (dashed arrows) from its mRNA targets, thus altering gene expression. Through interaction with U1 snRNP, exon-intron circRNAs (EIciRNAs) can interact with transcription complexes at host genes to induce their transcription lncRNA MALAT1/miR-328 axis promotes the proliferation They play an essential role in regulating gene expression and imatinib resistance of CML cells, providing new per- [151] through forming covalently closed continuous loop spectives for the future study of MALAT1 as a therapeutic structures with no exposed ends. CircRNAs are evolution- target for CML [40]. In addition, miR-214 was associated arily conserved, display a higher degree of relative stability with the imatinib resistance in CML patients by regulating in the cytoplasm and are often expressed in a tissue/devel- ABCB1 expression [143].miR-30e has been shown to be opmental stage-specific trend [152]. Briefly, circRNAs are directly targeting ABL mRNA and leads to decreased trans- produced co-transcriptionally from precursor mRNA by lation of ABL protein [144]. In K562 cells, the increased ex- back-splicing of RNA polymerase II transcribed genes and pression of miRNA-30e induces apoptosis and suppresses often expressed at only low levels. The biogenesis of cir- proliferation and sensitized the cells to imatinib treatment. cRNAs is regulated through cis and trans-acting regula- miR-203 enhances the sensitivity of CML patients to ima- tory elements that control splicing [153]. The structural tinib and its expression was downregulated in bone marrow form of most circRNAs is composed of multiple exons, of CML patients [145]. and multiple circRNA isoforms can be expressed from a gene with the inclusion or exclusion of internal introns Circular RNAs through alternative splicing [153–155]. Circular RNAs (circRNAs) are an abundant class of regu- Recent studies have shown that several circRNAs latory transcripts primarily derived from protein-coding play important physiological and functional roles at exons and widely expressed across eukaryotic organisms, multiple stages of the gene expression regulation cas- including Homo sapiens and Mus musculus [146–150]. cade [84, 100, 101]. CircRNAs are known to be Bhat et al. Molecular Cancer (2020) 19:57 Page 10 of 21

involved in post-transcriptional regulation by acting have indicated a substantial genetic control of the circu- as decoys for binding of micro RNAs, reducing their lar RNA expression that is mostly independent of the cellular availability and resulting in the upregulation basal gene expression [173]. The power to distinguish of their target mRNAs (Fig. 4). For example, circRNA between tumor subtypes along with an independent gen- ciRS-7, also known as CDR1as, is produced from the etic control mechanism for their expression strongly vertebrate cerebellar degeneration-related 1 (CDR1) points towards a functional and regulatory role for the antisense transcript and acts as an RNA sponge to re- circular RNA structures and their potential to contribute press miR-7 activity [148, 156]. Knockout mice of to disease pathogenicity. It is, therefore, worthwhile to CDR1as show defects in sensorimotor gating [157] investigate the mechanisms for biogenesis of circRNAs and knockdown of CDR1as expression results in a de- and their contribution to pathogenesis; this may lead to crease of tumor growth and proliferation in cancer the development of new therapeutic interventions and cell lines [158, 159]. Another circular RNA produced biomarkers with diagnostic and prognostic capabilities. from the Sry gene has 16 binding sites for miR-138, and overexpression constructs of Sry circRNA attenuate the Underlying mechanisms of chemoresistance knockdown effects of miR-138 target mRNAs [156]. In- regulated by ncRNAs in leukemia deed, multiple studies have remarkably demonstrated the As in many cancers, resistance to therapy is a significant potent sequestering effects of miRNA activity by cir- problem in the treatment of leukemia patients. The most cRNAs, making them excellent agents for competing en- commonly used chemotherapeutic drugs like bendamus- dogenous RNA activity [148, 156, 160–164]. Increasing tine, chlorambucil, and rituximab [174, 175]although evidence also suggests that circular RNAs could perform show initial response, but later on patients acquire resist- other functional roles such as storage or sequestration of ance to these therapeutic regimens, hence limiting their transcription factors and RNA binding proteins [165], efficacy. Also, many leukemia patients show resistance be- microRNA transport [157] or encode functional proteins fore treatment (intrinsic resistance) and therefore do not [166–169]. even show initial response. While the molecular mecha- CircRNAs are altered in a variety of pathological con- nisms for both intrinsic and acquired resistance are mostly ditions, which has stimulated significant interest in their unidentified, identification of unique targets and pathways role in human disease and cancer. There is emerging involved are still an area of intense investigation. Though evidence that circRNAs show close association with genetic and epigenetic modifications that result in dysreg- many human diseases, including cancers – often but not ulation of multi drugs transporters, alterations of drug tar- always involving micro RNA (miRNA) intermediate. gets & metabolism of drugs, defects in apoptosis & One study revealed hundreds of circRNAs being more autophagy machinery, disruption of redox system, in- abundant in blood than corresponding linear mRNAs, creased DNA repair and increased stem cell populations. which suggests that circRNAs could be used as new bio- Have been identified as mediators of drug resistance, the markers in standard clinical blood samples [170]. For in- exact mechanisms of drug resistance, cross-talk among stance, circ-CBFB was found to promote proliferation different mechanisms and their regulation are still under and inhibit apoptosis in CML by regulating the miR- investigation. Recently, studies have conclusively estab- 607/FZD3/Wnt/beta-catenin pathway [171]. Addition- lished the role of miRNAs in chemotherapeutic resistance ally, circ_0009910 was found to be significantly upregu- in leukemia [176, 177]. These studies have shown the de- lated in AML patients, and its high expression was regulation of many miRNAs and their association with re- shown to be associated with poor outcomes of AML pa- sistance to chemotherapy. For example, miR-181a and tients [68]. Similarly, hsa_circ_0080145 was found to miR-181b are downregulated in chronic lymphocytic regulate CML cell proliferation by acting as a miR-29b leukemia (CLL) [138] and overexpression of these miR- sponge, and its knockdown was found to suppress CML NAs sensitize CLL cells to fludarabine mediated cell death cell proliferation [170] significantly. On the other hand, by targeting B-cell lymphoma − 2(BCL− 2), myeloid cell circRNAs circ_0132266 and hsa_circ_0004277 were leukemia-1 (MCL-1) and X-linked inhibitor of apoptosis found to be significantly downregulated in CLL and protein (XIAP) [178]. Similarly, restoration of miR-181b AML, respectively [63, 65]. sensitize leukemia cells to doxorubicin (DOX) and cytara- We have identified multiple circular RNAs that are bine (ara-C) by downregulating MCL-1 and high mobility differentially expressed in metastatic versus primary group box-1 (HMGB1) expression [179]. On the contrary, ovarian tumors [172]. These circRNAs exhibits a robust ectopic overexpression of miR-125b in leukemia cells in- expression pattern compared to their linear counterparts duced resistance to daunorubicin (DNR) and prevented with higher power to distinguish between tumor sub- apoptosis by downregulating G-protein-coupled receptor types. This may offer a more robust diagnostic marker kinase 2 (GRK2) and p53 -upregulated modulator of of disease progression and prognosis. Our new results apoptosis (PUMA) [180]. Bhat et al. Molecular Cancer (2020) 19:57 Page 11 of 21

Chronic myeloid leukocyte (CML) is characterized by cells by targeting ataxia telangiectasia mutated (ATM) the Philadelphia (Ph) chromosome [181] with fusion increased proliferation [139]. Also, miR-128 by targeting protein breakpoint cluster region-Abelson murine Rad51 promoted DNA damage and sensitized AML leukemia (BCR-ABL) tyrosine kinase overexpression. OCI-AML3 and MV4–11 cells to oral nucleoside analog Interestingly, Imatinib, an inhibitor of BCR-ABL, show prodrug called sapacitabine [196]. Though upregulated improved therapeutic efficacy in Ph-positive CML pa- in many cancers, miR-128 is downregulated in AML, es- tients [182]. Interestingly, downregulation of ABL target- pecially carrying NPM1 mutations [141, 197]. However, ing miRNA-30e was reported in CML cell lines and ectopic overexpression of miR-128 in HL60 cells in- patient samples [182]. Furthermore, overexpression of creased drug sensitivity and promoted apoptosis [140]. miRNA-30e in K562 leukemia cells suppressed prolifera- In addition to miR-128, other miRNAs such as miR-103, tion, induced apoptosis and sensitized them to Imatinib miR-107, and miR-506 have been found to target Rad51 treatment. While miRNA-203 sensitizes CML cells to in other cancers as well. More specifically, miRNA-125b Imanitib and induces apoptosis [145], miRNA-486, on is overexpressed in pediatric acute promyelocytic the other hand, promotes Imanitib resistance by target- leukemia (APL) than in other subtypes of acute myelog- ing PTEN and FOXO1 [183]. enous leukemia (AML), and its exogenous expression in While the intrinsic resistance is due to many factors, AML cells imparted DOX resistance [198]. including miRNA in our case, acquired resistance by ABC transporters are most important proteins pro- tumor cells is promoted in response to continuous drug moting drug resistance in almost all the tumors. While treatment. DNR and ara-C (anthracyclines) are most the above mentioned miRNAs impart drug resistance, commonly used and effective chemotherapeutic drugs many other miRNAs that are involved in sensitizing can- for leukemia treatment [184]. Though the use of these cer cells to therapeutic drugs by targeting ABC trans- drugs results in the complete remission of the disease, porters are downregulated in cancer [199]. In this most of the patients relapse within 5 years [185, 186], category, miR-326 was found to downregulate the ABC while inefficient tumor cell targeting, mutagenic effects transporter ABCC144 in resistant HepG2 cells and of the drug or selection of resistant clones might be the sensitize them to chemotherapeutic drugs. In addition to reasons for relapse and development of aggressive tu- ABCC144, miR-326 also negatively regulated other ABC mors, however the underlying mechanism(s) are still to family members such as ABCA2 and ABCA3, which are be identified. These anthracyclines by intercalating into drug-resistance related genes [200]. However, the miR- the DNA and targeting Topoisomerase II [187, 188] hin- 326 expression is reported to be significantly downregu- der replication [189]. Interestingly, Topoisomerase II is lated in the multidrug resistance (MDR+) pediatric ALL downregulated in drug-resistant AML subtypes [190, patients compared to the (MRD-) group [27]. A recent 191], thus making these tumors resistant to these drugs. study showed upregulation of miR-125b-2 cluster (Let- The topoisomerase II cuts DNA strands and binds to 7c, miR-125b, and miR-99a) in leukemia patients with + the scaffold/matrix-associated protein region (S/MAR) ETV6-RUNX1 fusion gene expression. to prevent or resolve DNA supercoils. Therefore, anthra- Further studies showed that knockdown of miR-125b + cycline treatment results in DNA double-strand breaks in REH ETV6-RUNX1 cells result in increased sensitiv- which can be temporarily fixed by non-homologous end ity to staurosporine and doxorubicin treatment, while joining leading to gene mutation and t4:11 is a common overexpression of miR-125b-2 cluster inhibited apoptosis mutation that occurs at S/MAR in AML [192–194]. S/ and increased cell survival suggesting its therapeutic po- MARs by interacting with HDACs regulate expression of tential in pediatric ALL [201]. In a recent comprehensive miRNAs like miR-93, miR-221, miR-17, let-7b and miR- study, the involvement of miRNAs in L-asparaginase (L- 17-92 cluster. While the dislocation or loss of S/MAR ASP), vincristine (VCR), prednisolone (PRED) and DNR can modulate miRNAs expression [195], anthracyclines resistance was investigated [202]. This study showed the like daunorubicin can induce DNA damage associated involvement of miR-454 in resistance to L-ASP, miR- with deregulation of miRNA expression in leukemia. 125b, miR-99a, & miR-100 to DNR and miR-125b to Though anthracyclines by modulating miRNA expres- VCR resistance. Furthermore, over expression of miR- sion regulate cell proliferation and apoptosis, specific 125b prevented VCR mediated apoptosis in vitro [202]. miRNAs modulate the DNA repair signaling pathway Interestingly, leukemia ETV6-RUNX1+ patients with components resulting in the development of therapeutic high expression of miR-125b show resistance to VCR resistance. In this connection, resistance to daunorubicin treatment. Like chemotherapeutic drugs, use of gluco- (DNR) has been associated with overexpression of corticoids (GCs) for clinical treatment of pediatric ALL miRNA-21 and its downregulation in resistant K562/ is also limited by the development of resistance resulting DNR cells enhanced DNR cytotoxicity in vitro. Similarly, in poor patient response. Involvement of miRNAs in re- overexpression of miR-181a in HL60, NB4, and K562 sistance/sensitivity to GC treatment has recently been Bhat et al. Molecular Cancer (2020) 19:57 Page 12 of 21

evaluated [203]. In a genome-wide study, while the ex- (ATRA) revealed significant alterations in leukocyte medi- pression of miR-335 was found to be downregulated in ated immunity, MHC class I protein complex, comple- all pediatric ALL patients, its overexpression sensitized ment control module and regulation of leukocyte ALL cells to PRED treatment in vitro [204]. In addition activation pathways [53]. Furthermore, HOTAIRM1 ex- to PRED, ALL cells with miR-335 overexpression pression is also modulated by another transcription factor, showed resistance to other chemotherapeutic drugs with PU.1, during granulocyte differentiation [208]. PU.1 is a limited cell death [204]. Another miRNA, miR-210 is master regulator of myeloid differentiation, while PU.1, differentially expressed in various types of cancers in- along with IRF8, is known to control the fates of follicular cluding leukemia [205]. Using agomiR or antagomiR for (FO) and germinal centers (GO) B cells [209]. Double miR-210 in LEH cells (to either increase or decrease the knockout of IRF8 and PU.1 in B cells has been shown to expression respectively) modulated the response to dexa- impair the development of FO and GC B cells [209]. This methasone (DEX), L-ASP, VCR and DNR [205], suggest- signifies that HOTAIRM1 can modulate tumor immunity ing that use of agomiR’s/antagomiR’s can be a novel in leukemia by interacting with other regulatory mole- alternative to overcome miRNA mediated therapeutic cules. PU.1 is also known to drive the expression of lnc- resistance in cancers including leukemia [205]. DC, which is a lncRNA exclusively expressed in human dendritic cells (DCs) and is required for the differentiation Role of non-coding RNAs in immune modulation of DCs [210]. Knockdown of lnc-DC resulted in impaired in leukemia DC differentiation and function, and these effects were Several ncRNAs, including miRNAs, lncRNAs and cir- mediated by lnc-DC by regulating the posttranslational cRNAs have been implicated in the modulation of the im- modification of a critical DC transcription factor, STAT3 mune system in various human malignancies, including [210]. Some of the proteins found to be altered after lnc- leukemia. These ncRNAs can modulate immune system DC knockdown include those involved in antigen presen- either directly by regulating the differentiation of immune tation (HLA-DR), cytokine secretion (IL-12) and T cell ac- cells or indirectly by regulating the expression of various tivation (CD40, CD80, and CD86). PU.1 also induces miR- signaling molecules, including NF-kB, c-Myc, p53 and 23-27-24 cluster and plays a vital role in the regulation of Notch. In this section, we will discuss the available evi- immune cell lineage commitment [211]. dence on the role of ncRNAs in immune modulation and Furthermore, this miRNA cluster regulates lymphoid its implications in leukemia. Most leukemia are driven by cell differentiation and promotes myeloid lineage com- genetic or epigenetic abnormalities in hematopoietic stem mitment and cell proliferation by directly targeting vari- cells (HSCs) or progenitor cells, leading to differentiation ous lymphoid transcription factors, including Runx1 arrest and increased proliferation and survival of imma- [211]. A recent study has identified a lincRNA, ture blasts in the bone marrow. In one of the first studies LINC00173, to be very specifically expressed in mature on understanding the role of lncRNAs in early granulocytes [212]. Knockdown of LINC00173 in human hematopoietic differentiation, RNA sequencing of HSCs CD34+ HSCs resulted in a defect in granulocytic differ- led to the identification of two lncRNAs, lncHSC-1 and entiation and an increase in myeloid precursors in vitro lncHSC-2 [206]. Their depletion resulted in altered mye- [212]. Depletion of LINC00173 in NB4 leukemia cells, loid differentiation, impaired self-renewal of HSCs and in- which carry an intrinsic block of granulocytic differenti- creased T cell differentiation [206]. These results indicate ation, resulted in reduced cell proliferation, signifying its that lncRNAs can regulate HSC differentiation, and any role in early myelopoiesis [212]. Functional studies re- deregulation in their expression might contribute to vari- vealed the binding of LINC00173 with the EZH2 subunit ous hematological malignancies by altering the differenti- of PRC2 [212]. X-inactive specific transcript (Xist) is an- ation of various HSCs. Indeed, several ncRNAs have been other lncRNA reported in various human malignancies, found to contribute to leukemogenesis through immune including leukemia. Conditional knockout of Xist in modulation and altering cell differentiation. HOXA tran- murine hematopoietic cells resulted in myeloid leukemia script antisense RNA, myeloid-specific 1 (HOTAIRM1) is and other impairments such as bone marrow dysfunc- a myeloid-specific long intergenic non-coding RNA tion, lymphoid organomegaly and lymphoid infiltration (lincRNA), and it is upregulated during myeloid matur- of end organs [213]. Aforementioned examples ation [207]. Knockdown of HOTAIRM1 in the human emphasize the importance of ncRNAs in regulating im- acute promyelocytic leukemia (APL) cell line NB4 resulted mune cell differentiation, which is of great clinical rele- in decreased granulocytic maturation [53]. HOTAIRM1 is vance in leukemia. known to regulate the expression of the HOX, CD11b and The tumor suppressor p53 is known to induce the ex- CD18 genes, which are required for myeloid cell differen- pression of lncRNA activator of enhancer domains (LED) tiation [53]. Pathway analysis of HOTAIRM1 knockdown in cancer [214]. The expression of LED is downregulated NB4 cells treated or untreated with all-trans retinoic acid in leukemia, possibly due to promoter hypermethylation Bhat et al. Molecular Cancer (2020) 19:57 Page 13 of 21

[214]. Another lncRNA, encoded from the first intron of transcribed from the upstream region of the human COX- the human p53 gene and known as lncRNAp53int1, is 2 gene, regulates COX-2 expression by interacting with shown to be highly expressed in undifferentiated human the repressive p50 subunit of NF-kβ, thereby functioning myeloid leukemia cells [215]. However, expression of as a decoy lncRNA for NF-kB signaling [225]. NF-kB in- lncRNAp53int1 is significantly reduced during terminal duced lncRNA, linc-Cox2, coactivates NF-kB, leading to differentiation of human leukemia cells into monocytes induction of late-primary response genes in innate im- and macrophages [215]. Since several drugs have been mune cells [226]. Since the NF-kβ family of transcription used to induce differentiation of leukemia cells, targeting factors plays a crucial role in the regulation of tumor in- of lncRNAp53int1 could offer a newer therapeutic ap- flammation and immunity [227], we suggest that the NF- proach for the management of leukemias. Induction of kβ as mentioned above regulated ncRNAs might also p53 has also been shown to induce two other lncRNAs, modulate immune system in leukemia. nuclear enriched abundant transcript 1 (NEAT1) and Notch-regulated oncogenic lncRNA, leukemia-induced lincRNA-p21, in primary human CLL [216]. The expres- non-coding activator RNA-1 (LUNAR1), has been iden- sion of NEAT1 is downregulated and seems to be regu- tified in T-cell acute lymphoblastic leukemia (T-ALL) lated by PML-RARα in APL [217]. NEAT1 is also found [228]. Mechanistically, LUNAR1 regulates IGF signaling to regulate myeloid differentiation in APL [217]. Recently, and induces IGF1R expression, leading to the survival of pharmacological activation of p53 has been shown to in- T-ALL cells [228]. The expression of LUNAR1 is upreg- duce an immune-inflammatory response by activating NK ulated in primary T-ALL cells, more so in Notch mu- cells, leading to suppression of leukemia growth [218]. tated samples, whereas its expression is suppressed upon However, p53 activation also results in the overexpression Notch inhibition [228]. Another lncRNA, NOTCH1 as- of PD-L1 in the surviving leukemia cells, promoting their sociated lncRNA in T ALL (NALT), is also found to be immune escape [218]. All these evidences suggest a crucial associated with the Notch1 gene and functions as a tran- role of p53 in regulating lncRNAs during immune modu- scription factor to activate Notch signaling and promote lation in leukemia. cell proliferation in pediatric T-ALL cells [229]. Role of Enhancer RNAs (eRNAs) are another class of lncRNAs Notch signaling in normal and effector immune cell dif- and have been reported to be involved in immune ferentiation is well established [230]. Furthermore, modulation. Brazao et al. identified three lncRNA loci Notch can regulate various components of TME, includ- (LNCGme00432, LNCGme00344 and LNCGme00345), ing immune cells, fibroblasts, endothelial, and mesen- all of which are eRNAs, in a mouse model of B-ALL chymal cells [230]. Since Notch signaling is also involved [219]. All of these eRNAs interact with PAX5, a tran- in human T-ALL [228, 229], we believe that Notch- scription factor required for B-cell development and as- regulated lncRNAs can potentially modulate immune sociated with the development of B-ALL, and are system in leukemia. downstream of the B-cell lymphoma 11a (Bcl11a) gene Beta Globin Locus 3 (BGL3) is a lncRNA that regu- [219]. Since the Bcl11a gene is required for VDJ recom- lates Bcr-Abl mediated cellular transformation in CML bination of immunoglobin genes and is also involved in [57]. Bcr-Abl has been found to negatively regulated B-cell development, a role of these eRNAs along with BGL3 expression through c-Myc-dependent DNA the PAX5 and Bcl11a genes in normal B-cell develop- methylation in CML [57]. Interestingly, BGL3 acts as a ment and immune modulation in B-ALL cannot be competitive endogenous RNA (ceRNA), and it is tar- ruled out. geted by many PTEN regulating miRNAs, including In CLL, more than 50% of cases carry a deletion of the miR-17, miR-93, miR-20a, miR-20b, miR-106a and miR- critical region at 13q14.3 [220, 221]. In addition to various 106b [57]. It is well known that loss of PTEN in cancer tumor suppressor genes, miR-15a/16–1 and lncRNAs, de- cells leads to an immunosuppressive microenvironment leted in lymphocytic leukemia 1 (DLEU1) and 2 (DLEU2), through secretion of various immunosuppressive cyto- are also transcribed from this locus [222]. The miRNAs kines, recruitment of myeloid-derive suppressor cells and lncRNAs have been reported to be deleted and epige- (MDSCs) and regulatory T-cells (Tregs), and inhibition netically regulated in CLL [222, 223]. Interestingly, of CD8+ T-cell killing [231]. Hence, we speculate that DLEU1 and DLEU2 are also known to regulate NF-kB ac- BGL3 might also lead to immune modulation in tivity through other NF-kβ regulating genes. Furthermore, leukemia through PTEN and PTEN-regulating miRNAs, the miR-15/16 family of genes is also known to induce although this needs to be experimentally proven. Colon NF-kβ activity [222] strongly. In CLL, NF-kB signaling is cancer-associated transcript-1 (CCAT1) is a lncRNA reported to be active, usually through interaction with the that is known to be highly expressed in adult AML tumor microenvironment (TME), which leads to the sur- [153]. CCAT1 represses monocytic differentiation and vival of leukemia cells [224]. Another lncRNA, p50- promotes leukemia cell growth by upregulating onco- associated COX-2, extragenic RNA (PACER), which is genic c-Myc and suppressing tumor suppressive miR- Bhat et al. Molecular Cancer (2020) 19:57 Page 14 of 21

155 [153]. c-Myc is also known to induce lncRNA H19 cells [85]. The miR-17-92 cluster, which encodes six expression in leukemia cells, thereby promoting cell pro- miRNAs including 17, 18a, 19a, 20a, 19b-1, and 92–1, is liferation and survival [232]. Plasmacytoma variant also known to regulate T-cell responses in graft-versus- translocation 1 (PVT1) is another lncRNA that exerts its host disease (GVHD) post allogeneic bone marrow oncogenic effects by stabilizing the c-Myc protein in transplantation in mice [237]. This miRNA cluster has cancer [233]. Furthermore, in leukemia and other solid been found to promote CD4 T-cell activation, expan- tumors, c-Myc is known to induce the expression of sion, migration and Th1 differentiation while suppress- cluster of differentiation 47 (CD47), an innate immune ing Th2 and Treg differentiation. Inhibition of miR-17 regulator, and programmed death-ligand 1 (PD-L1), an or miR-19b significantly inhibited alloreactive T-cell ex- adaptive immune checkpoint protein, involved in sup- pansion and IFN-γ secretion, leading to prolonged sur- pressing the antitumor immune response [234]. Hence, vival in recipient mice with GVHD while preserving the we believe that lncRNAs regulated by c-Myc might also graft-versus-leukemia effect [237]. Overexpression of modulate the immune response in leukemia. miR-125a-5p has been shown to induce granulocytic dif- Recent evidence also suggests a crucial role of cir- ferentiation, whereas miR-17-92 has the opposite effect cRNAs in immune modulation and leukemia develop- in APL cells [238]. A recent study has identified overex- ment. The presence of fusion circRNAs (F-circRNAs) pression of miR-708 in AML patients, which delayed has been shown in PML/RARα positive APL and MLL/ HOXA9 mediated transformation in vivo by modulating AF9 positive AML cells [58]. These F-circRNAs not only myeloid differentiation [239]. The authors concluded caused cellular transformation by activating PI3K and that miR-708 is an indirect regulator of the HOX pro- MAPK signaling but also contributed to leukemia cell gram during normal and impaired hematopoiesis [239]. proliferation, survival, progression and therapy resistance in vivo [58]. Since immune cells also regulates cell prolif- Clinical significance of ncRNAs in leukemia eration, survival and confer resistance to therapy, we be- In the current exploratory genomic era, the cellular or lieve that oncogenic F-circRNAs might also be involved extracellular level of noncoding RNAs (ncRNAs) are ad- in modulating the host immune system in leukemia, giv- vancing for their roles in risk stratification, diagnosis, ing a survival advantage to leukemia cells. Because the and prognosis. Biologically ncRNAs regulate different presence of circRNAs has also been detected in extracel- processes such as proliferation, apoptosis, stemness, and lular vesicles [91], these circRNAs may modulate TME differentiation. The clinical significance of ncRNAs in through cell-to-cell communication, although this is yet leukemia broadly illustrates their capability for risk to be experimentally proven. Another circRNA, hsa_ stratification, diagnosis, and prognosis [212, 240, 241]. circ_0075001, has been detected in AML where its ex- The quantitative assessments of transcripts by highly pression positively correlated with total NPM1 expres- sensitive assay (qPCR) for minimal residual disease de- sion [60]. AML patients carrying a high expression of tection make ncRNA as a suitable candidate biomarker. hsa_circ_0075001 had lower expression of components The residual transcript copies play a significant role in of the Toll-like receptor signaling pathway, suggesting detecting minimal residual disease. The best analogy is that this circRNA might be involved in the modulation BCR-ABL international scale detection for deep molecu- oftheimmuneresponseinAML[60]. Another cir- lar and ultra-deep molecular response in Philadelphia cRNA, circMYBL2, which is derived from the cell- positive leukemias. cycle checkpoint gene MYBL2, has been reported to The prerequisite for ncRNAs as biomarkers in be highly expressed in FLT3-ITD mutation-positive leukemia is their aberrant expression in leukemic pheno- AML patients [235]. Depletion of circMYBL2 inhib- type., A plethora of differential miRNA, lncRNA and cir- ited proliferation and induced differentiation of FLT3- cRNAs from high throughput data, supported the notion ITD AML cells in vitro and in vivo [235]. In a recent and met this primary concern. However, leukemia itself study of a comprehensive analysis of circRNA expres- is a disease of heterogeneous cell population; therefore, sion during hematopoiesis, the expression of circRNA precisely identifying the robust biomarker in variable was found to be highly cell-type specific during data sets of different leukemia subtype is very challen- hematopoietic differentiation [236]. All these studies ging at the validation step. Furthermore, the ncRNA highlight the crucial role of circRNAs in immune fine-tune the cellular homeostasis; therefore their regula- modulation in leukemias. tory function activated with a slight change in the onco- Several miRNAs have been shown to modulate im- genic molecular thrust. The ncRNAs modulates and mune checkpoint proteins in various human malignan- attempt to reconcile the abnormal molecular changes. cies, including leukemia. In AML, miR-34 regulates PD- Recently, three-lncRNA expression-based risk score was L1 expression by targeting PD-L1 mRNA, thereby con- developed based on RNA-seq data for AML patients trolling PD-L1 specific T-cell apoptosis of human AML using two leading data repositories [Therapeutically Bhat et al. Molecular Cancer (2020) 19:57 Page 15 of 21

Available Research to Generate Effective Treatments thereby, it acts as tumor suppressor gene, and this find- (TARGET) and The Cancer Genome Atlas (TCGA)]. ing was confirmed in 68 CLL patients, 62 MM patients According to prognosis modelling, which was developed when compared with 36 healthy controls. The correl- based on survival data, the combination of the lncRNA ation of p53 repression through LincRNA-p21 makes it risk score and cytogenetics risk group provided a higher eligible therapeutic and prognostic marker in CLL pa- prognostic value than any of the individual prognostic tients [216, 244]. factor [61]. BGL3 lncRNA regulates the oncogenic expression of Acute myeloid leukemia is a heterogenous malignancy BCR-ABL fusion gene through c-Myc mediated signal- of defective stem cells with impaired proliferation and ing. The expression of BGL3 gene was inversely regu- differentiation. Many regulatory ncRNAs largely regulate lated through miR-17, miR-93, miR-20a, miR-20b, miR- the deregulation, stemness, proliferation and differenti- 106a, and miR-106b in Philadelphia positive ALL and ation. Various studies have proved that many deregu- CML patients [57, 245]. lated miRNAs are correlated with acute leukemia as Non-coding microRNAs (miRNAs) are posttranscrip- compared to control samples. Table 1 shows a list of sig- tional and posttranslational regulators of the target nificant ncRNAs (lncRNA and circRNAs) for their genes and proteins, respectively. The expression and pathological and clinical significance in leukemia. modulation of target genes is disease and tissue-specific. HOTAIRM1 is located between HOXA1 and HOXA2 In leukemia, miRNA expression signature depends upon gene cluster and regulate granulocytic differentiation in the disease subtype, cytogenetic risk group, age and mo- hematopoiesis. High HOTAIRM1 expression results in lecular lesions like fusion genes or various mutations in increased expression of HOXA4 gene expression and de- a gene like FLT3, cKIT, NPM1, BCR-ABL, MLL re- fective myelopoiesis. HOTAIRM1 knockdown experi- arrangement. The most frequently deregulated miRNAs ments on NB4 cells correlated with low expression of in CML include miR-10a, miR-17/92, miR-150, miR-203, HOXA1 and HOXA4 cluster genes and block the ex- and miR-328. Oncogenic role of miR-9 was suggested by pression of CD11b and CD18 during granulopoiesis. Chen et al. in the subgroup of AML patients with mixed HOTAIRM1 expression is activated by all-trans retinoic lineage leukemia (MLL)-rearrangement [246]. However, acid, which induces the differentiation of myeloid pro- Emmrich et al. suggested tumor suppressor role and ex- genitor cells to granulocytes and mature myeloid cells pression was down-regulated in pediatric AML with t (8; [53]. HOTAIRM1 transcript also interacts and form 21) translocation [247]. A similar finding was observed complexes with transcripts of other key chromatin struc- in Fu et al. that miR-9-1 was down-regulated in t (8;21) ture modulating proteins such as CBX1, PRC1 and AML patients [248]. Many recent studies have compiled PRC2 [242]. HOTAIRM1 was overexpressed in NPM1- the biological and clinical significance of miRNAs in mutated AML. Furthermore amongst, 215, intermediate acute and chronic leukemia [10, 240, 241]. cytogenetics risk group AML patients, high HOTAIRM1 Like lncRNA and miRNA, circular RNAs (circRNAs) expression was associated with inferior overall survival express as housekeeping, and regulatory RNAs. The (OR: 2.04; P = 0.001) and disease-free survival (OR:2.56; mode of action of circRNA may be autocrine or para- P < 0.001) and a higher cumulative incidence of relapse crine; therefore, these circRNAs have been detected in (OR:1.67; P = 0.046). Furthermore, high expression of various body fluids. The circRNAs are stable in different HOTAIRM1 was associated with poor survival outcome body fluids like saliva, urine, blood, and CSF. The basal in the subgroup of NPM1 mutation-positive AML pa- level of various circRNAs is crucial to explore for under- tients [54]. HOXA-AS2: HOXA cluster antisense RNA 2 standing their clinical significance. In leukemia, ultra- (HOXA-AS2) located between HOXA3 and HOXA4 deep genomic data is available, which enabled to explore genes in the HOXA cluster. Like HOTAIR and different ncRNA entities for their diagnostic and prog- HOTAIRM1, HOXA-AS2 regulates differentiation of nostic significance. Various types of circRNAs have been myeloblasts to mature granulocytes and myeloid cells characterized based on their position in the gene, the in- [243]. Dong et al. proved the important role of HOXA- tron origin circRNA and exonic circRNAs, intergenic AS2 in chemoresistance of myeloblast and the lncRNA circRNAs, and exon-intron circRNAs. Although, a vari- HOXA-AS2 could act as a therapeutic target for over- ous study has supported the notion of differential cir- coming resistance to chemotherapy in AML [96]. cRNA expression profile in leukemia but the validation DLEU1 and DLEU2 lncRNA mapped on the frequently data from experimental studies is limited.. The origin of deleted region of chromosome 3q14.3 region in lymph- circRNAs has been associated with fusion genes in oma and leukemia. DLEU2 lncRNA act as pre miRNA leukemia [249]. Isolated studies have shown the role of for 15a and 16–1 and both are involved in the pathogen- following cirRNAs, f-circPR, f-circM9, hsa_circ_0075001, esis of CLL through NF-kβ activity [222, 223]. LincRNA- circ-ANAPC7, circ-100,290, circPAN3, circ_0009910, p21 in CLL is associated with p53 gene repression; circ-HIPK2, circ-DLEU2, has_cir_0004277, circPVT1 in Bhat et al. Molecular Cancer (2020) 19:57 Page 16 of 21

AML [59, 71, 250–252]. In CML, the direct association by synthetically modifying themto reduce the oncogenic of circBA9.3 with BCR-ABL tyrosine kinase activity was lncRNAs by alternative splicing, modulation of RNA and observed in CML patients. The high expression of cir- protein interactions or by degrading them. Further, lenti- cBA9.3 was associated with cell proliferation and inverse viral vectors can be used as an efficient method for the relations with apoptosis. Furthermore, the high expres- transportation of RNA products into tissues as they aid sion was associated with relapse and disease progression in stable transfection by efficiently inserting the siRNA suggesting the possible role of circBA9.3 as a potential sequence into target cells. therapeutic marker in CML [72]. Regarding the many roles of ncRNAs in cancer, there are still many challenges that must be resolved in order Conclusions & future perspectives to improve the potential of ncRNAs as a potential thera- The crucial role of ncRNAs in the gene regulatory net- peutic target in cancer. As the complex microenviron- works and recent progress in the field of genomics and ment of the cell makes the delivery of ncRNAs very biotechnology has made them a favorable therapeutic challenging and difficult, the efficient delivery system targeting agent in cancer. lncRNAs and circRNAs act with minimal toxicity is vital. It is suggested that the through various mechanisms as compared to miRNAs in drug delivery can be improved by using two or more dif- cancer, and so targeting them can help in exploring ferent carriers for targeting ncRNAs, for example com- more critical mechanisms involved in tumorigenesis. bining nano designs with organ-specific response This review highlights the therapeutic potential of receptor. Moreover, in order to increase their bioavail- ncRNAs such as miRNAs, lncRNAs and circRNAs in ability, different ways must be discovered to reduce RNA leukemia and culminates the significance of these bio- degradation. Although the field of ncRNAs is well stud- molecules as they improved the prognostic risk stratifi- ied, their role as a biomarker and as a therapeutic target cation in leukemia. The improvement in risk in cancer is yet to be explored in detail. Many clinical stratification has led to the generation of medical algo- trials are currently underway, and if some of the chal- rithms that can help in standardizing selection and treat- lenges mentioned above are addressed appropriately, ment planning based on the molecular profile of the then we would likely see ncRNAs emerging as a novel patient. These risk stratification schemes can be taken target for cancer therapy. one step further by the inclusion of selected ncRNA ex- pression profiles. Abbreviations ALL: Acute lymphoblastic leukemia; AML: Acute myeloid leukemia; ATRA: All- Additionally, by artificially modulating the expression trans retinoid acid; BCLAF1: BCL2-associated transcription factor 1; BGL3: Beta of ncRNAs, the therapeutic sensitivity to conventional Globin Locus 3; CD47: Cluster of differentiation 47; ceRNA: Endogenous RNA; chemotherapy can be restored. In this regard, miRNAs circRNA: Circular RNA; CLL: Chronic lymphoblastic leukemia; CML: Chronic myeloid leukemia; CRC: Colorectal cancer; DCs: Dendritic cells; have become the most extensively studied ncRNAs in DLEU1: Deleted in lymphocytic leukemia 1; DLEU2: Deleted in lymphocytic leukemia because of their role as an oncogene and leukemia 2; eRNAs: enhancer RNAs; GVHD: Graft-versus-host disease; tumor suppressor in various cancers, including leukemia HOTAIRM1: HOXA transcript antisense RNAs, myeloid-specific 1; HOXA- AS2: HOXA cluster antisense RNA2; lncRNA: long non-coding RNA; and their involvement in the regulation of post- MDR: Multidrug resistance; miRNA: microRNA; MSC: Mesenchymal stromal transcriptional processes. The advanced genomic ap- cells; ncRNA: non-coding RNA; NEAT1: Nuclear enriched abundant proaches, such as CRISPR-Cas9 technology is used to transcript 1; PD-L1: Programmed death-ligand 1; PI3K: Phosphoinositide-3 kinase; PRC2: Poly-comb repressive complex-2; pre-miRNA: precursor miRNAs; identify functionally relevant miRNA-mRNA target pairs Pri-miRNA: Primary miRNA; PVT1: Plasmacytoma variant translocation 1; that regulate leukemia (e.g., AML) cell line growth and siRNAs: small interfering RNAs; TME: Tumor microenvironment will likely prove beneficial for preclinical models. An- other approach is the use of miRNA mimics or modified Acknowledgements MH is supported by Sidra Medicine institutional funding. AAB is supported miRNAs as RNA based drugs to target ncRNAs and by Sidra Medicine internal grant (SIRF_20046) and SU is supported by mRNAs. Silencing of aberrant miRNAs can also be Medical Research Centre grants (grant# 16102/6, #16354/16). The authors achieved by miRNA sponges and anti-miRNA oligonu- would like to express their gratitude to Dr. Vineeta Tanwar (Research Scientist, Ohio State University, Ohio, Columbus, USA) for help in English cleotides (AMOs). Finally, miRNA analysis through ad- editing and valuable suggestions to improve the quality of the manuscript. vanced next-generation sequencing will provide more details on the involvement of ncRNAs in the onset and Authors’ contributions progression of leukemia. For efficient miRNA-based Conceptualization, AAB, SYN, MH and SU; writing—original draft preparation, AAB, SN, IA, RM, SKS, LZ, IE, SK, KSP, AQ, SK and SU; writing—review and therapy, improvised miRNA delivery vehicles with higher editing, AAB, SN, MH, MK, WER, HZ, MK and SU; Revision of manuscript, AAB, stability and less toxicity must be developed. SN, IA, RM, SKS, LZ, IE, SK, KSP, AQ,SK and SU supervision, AAB, SU, MH, SN, On the other hand, oncogenic lncRNAs can be tar- MK, WER and SU. All authors have read and approved the final version of the manuscript. geted using siRNAs by packaging them in nanoparticle vectors for efficient targeting. In addition, high affinity Funding or stability of antisense oligonucleotides can be achieved The authors declare that no funding support was received for this study. Bhat et al. Molecular Cancer (2020) 19:57 Page 17 of 21

Availability of data and materials 16. Chen S, et al. Long non-coding RNAs: the novel diagnostic biomarkers for Not applicable, please refer to the original reference. leukemia. Environ Toxicol Pharmacol. 2017;55:81–6. 17. Zebisch A, et al. Therapeutic Resistance in Acute Myeloid Leukemia: The Ethics approval and consent to participate Role of Non-Coding RNAs. Int J Mol Sci. 2016;17(12):2080. Not applicable, neither ethics approval was required for this review nor 18. Dell'Aversana C, et al. miR-194-5p/BCLAF1 deregulation in AML – involvement of patients. tumorigenesis. Leukemia. 2017;31(11):2315 25. 19. Wan L, et al. MicroRNA-103 confers the resistance to long-treatment of adriamycin to human leukemia cells by regulation of COP1. J Cell Biochem. Consent for publication 2018;119(5):3843–52. All authors consent to publication. 20. Ferreira AF, et al. ApoptomiRs expression modulated by BCR-ABL is linked to CML progression and imatinib resistance. Blood Cells Mol Dis. 2014; Competing interests 53(1–2):47–55. The authors declare that they have no competing interests. 21. Hu N, et al. MALAT1 knockdown inhibits proliferation and enhances cytarabine chemosensitivity by upregulating miR-96 in acute myeloid Author details leukemia cells. Biomed Pharmacother. 2019;112:108720. 1Translational Medicine, Sidra Medicine, P.O. Box 26999, Doha, Qatar. 22. Kotani A, et al. A novel mutation in the miR-128b gene reduces miRNA 2Department of Biomedical Science, College of Health Sciences, Qatar processing and leads to glucocorticoid resistance of MLL-AF4 acute University, Doha, Qatar. 3Translational Research Institute, Academic Health lymphocytic leukemia cells. Cell Cycle. 2010;9(6):1037–42. System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar. 4Laboratory 23. Li Q, Song W, Wang J. TUG1 confers Adriamycin resistance in acute myeloid for Stem Cell & Restorative Neurology, Era’s Lucknow Medical College and leukemia by epigenetically suppressing miR-34a expression via EZH2. Hospital, Lucknow, Uttar Pradesh, India. 5Department of Medical Lab Biomed Pharmacother. 2019;109:1793–801. Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk, 24. Huang Y, et al. Identification of serum miR-34a as a potential biomarker in Saudi Arabia. 6Department of Medical Oncology, Dr. B. R. Ambedkar Institute acute myeloid leukemia. Cancer Biomark. 2018;22(4):799–805. Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 25. Zhang J, et al. Differential expression profiles and functional analysis of India. 7Department of Biochemistry, Faculty of Science, University of Tabuk, plasma miRNAs associated with chronic myeloid leukemia phases. Future Tabuk, Saudi Arabia. 8Department of Surgery, University of Miami, Miami, Oncol. 2019;15(7):763–76. Florida, USA. 9Department of Biotechnology, Central University of Kashmir, 26. Zhang C, et al. Identification of miRNA-mRNA network associated with Ganderbal, Jammu and Kashmir, India. 10Laboratory Animal Research Center, acute myeloid Leukemia survival. Med Sci Monit. 2017;23:4705–14. Qatar University, Doha, Qatar. 27. Ghodousi ES, Rahgozar S. MicroRNA-326 and microRNA-200c: two novel biomarkers for diagnosis and prognosis of pediatric acute lymphoblastic Received: 15 December 2019 Accepted: 2 March 2020 leukemia. J Cell Biochem. 2018;119(7):6024–32. 28. Liu Y, et al. Decreased microRNA-30a levels are associated with enhanced ABL1 and BCR-ABL1 expression in chronic myeloid leukemia. Leuk Res. – References 2013;37(3):349 56. 1. Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J 29. El-Khazragy N, et al. miRNA-155 and miRNA-181a as prognostic biomarkers Med. 2015;373(12):1136–52. for pediatric acute lymphoblastic leukemia. J Cell Biochem. 2019;120(4): – 2. Ferlay J, et al. GLOBOCAN 2012 v1. 0, cancer incidence and mortality 6315 21. worldwide: IARC CancerBase No. 11. Lyon: International agency for research 30. Zhu X, et al. Functional studies of miR-130a on the inhibitory pathways of on cancer, 2013; 2016. apoptosis in patients with chronic myeloid leukemia. Cancer Gene Ther. – 3. Rodriguez-Abreu D, Bordoni A, Zucca E. Epidemiology of hematological 2015;22(12):573 80. malignancies. Ann Oncol. 2007;18(Suppl 1):i3–8. 31. Zhou L, et al. microRNA125b promotes leukemia cell resistance to – 4. Weinberg RA. The Biology of Cancer: Second International Student Edition. daunorubicin by inhibiting apoptosis. Mol Med Rep. 2014;9(5):1909 16. New York: Garland Science; 2013. 32. Zhou H, et al. Downregulation of miR-224 and let-7i contribute to cell 5. Swerdlow SH, International Agency for Research on Cancer. World Health survival and chemoresistance in chronic myeloid leukemia cells by Organization. WHO classification of tumours of haematopoietic and regulating ST3GAL IV expression. Gene. 2017;626:106–18. lymphoid tissues. Lyon: International Agency for Research on Cancer. 2008. 33. Zhao Q, et al. TCF7L2 activated HOXA-AS2 decreased the glucocorticoid 6. Ward E, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J sensitivity in acute lymphoblastic leukemia through regulating HOXA3/ Clin. 2014;64(2):83–103. EGFR/Ras/Raf/MEK/ERK pathway. Biomed Pharmacother. 2019;109:1640–9. 7. Chokkalingam AP, Buffler PA. Genetic susceptibility to childhood leukaemia. 34. Wang X, et al. Long non-coding RNA taurine-upregulated gene 1 correlates Radiat Prot Dosim. 2008;132(2):119–29. with poor prognosis, induces cell proliferation, and represses cell apoptosis 8. Hubbard T, et al. The Ensembl genome database project. Nucleic Acids Res. via targeting aurora kinase a in adult acute myeloid leukemia. Ann Hematol. 2002;30(1):38–41. 2018;97(8):1375–89. 9. Cruz-Miranda GM, et al. Long Non-Coding RNA and Acute Leukemia. Int J 35. Wang Y. Comprehensive long non-coding RNA expression profiling by RNA Mol Sci. 2019;20(3). https://doi.org/10.3390/ijms20030735. sequencing reveals potential biomarkers for acute myeloid leukemia risk. 10. Liu Y, et al. Role of microRNAs, circRNAs and long noncoding RNAs in acute Cancer Biomark. 2019;26:93–108. myeloid leukemia. J Hematol Oncol. 2019;12(1):51. 36. Zhou X, et al. LncRNA MEG3 regulates Imatinib resistance in chronic myeloid 11. Handschuh L. Not only mutations matter: molecular picture of acute Leukemia via suppressing MicroRNA-21. Biomol Ther (Seoul). 2017;25(5):490–6. myeloid Leukemia emerging from transcriptome studies. J Oncol. 2019; 37. Yang L, et al. Overexpression of lncRNA PANDAR predicts adverse prognosis 2019:7239206. in acute myeloid leukemia. Cancer Manag Res. 2018;10:4999–5007. 12. Wang Y, et al. Long non-coding RNA LINC00899 as a novel serum 38. Yan H, et al. Long non-coding RNA GAS5 polymorphism predicts a poor biomarker for diagnosis and prognosis prediction of acute myeloid prognosis of acute myeloid leukemia in Chinese patients via affecting leukemia. Eur Rev Med Pharmacol Sci. 2018;22(21):7364–70. hematopoietic reconstitution. Leuk Lymphoma. 2017;58(8):1948–57. 13. Wang Y, Zhou Q, Ma JJ. High expression of lnc-CRNDE presents as a 39. Xiao Y, et al. lncRNA UCA1 contributes to Imatinib resistance by acting as a biomarker for acute myeloid leukemia and promotes the malignant ceRNA against miR-16 in chronic myeloid Leukemia cells. DNA Cell Biol. progression in acute myeloid leukemia cell line U937. Eur Rev Med 2017;36(1):18–25. Pharmacol Sci. 2018;22(3):763–70. 40. Wen F, et al. LncRNA MALAT1 promotes cell proliferation and imatinib 14. Li J, Sun CK. Long noncoding RNA SNHG5 is up-regulated and serves as a resistance by sponging miR-328 in chronic myelogenous leukemia. Biochem potential prognostic biomarker in acute myeloid leukemia. Eur Rev Med Biophys Res Commun. 2018;507(1–4):1–8. Pharmacol Sci. 2018;22(11):3342–7. 41. Zhang Y, Liu Y, Xu X. Knockdown of LncRNA-UCA1 suppresses 15. Lammens T, et al. Long non-coding RNAs in leukemia: biology and clinical chemoresistance of pediatric AML by inhibiting glycolysis through the impact. Curr Opin Hematol. 2017;24(4):353–8. microRNA-125a/hexokinase 2 pathway. J Cell Biochem. 2018;119(7):6296–308. Bhat et al. Molecular Cancer (2020) 19:57 Page 18 of 21

42. Yu J, et al. Genomewide profiling of lncRNA expression patterns in patients 68. Ping L, et al. Silencing of circ_0009910 inhibits acute myeloid leukemia cell with acute promyelocytic leukemia with differentiation therapy. Oncol Rep. growth through increasing miR-20a-5p. Blood Cell Mol Dis. 2019;75:41–7. 2018;40(3):1601–13. 69. Ping L, et al. High circ_100053 predicts a poor outcome for chronic myeloid 43. Wang H, et al. The role of long noncoding RNA HOTAIR in the acquired leukemia and is involved in imatinib resistance. Oncol Res. 2019. https://doi. multidrug resistance to imatinib in chronic myeloid leukemia cells. org/10.3727/096504018X15412701483326. Hematology. 2017;22(4):208–16. 70. Liu J, et al. Global identification of circular RNAs in chronic myeloid 44. Sun J, et al. A novel antisense long noncoding RNA within the IGF1R gene leukemia reveals hsa_circ_0080145 regulates cell proliferation by sponging locus is imprinted in hematopoietic malignancies. Nucleic Acids Res. 2014; miR-29b. Biochem Biophys Res Commun. 2018;504(4):660–5. 42(15):9588–601. 71. Chen H, et al. Circ-ANAPC7 is upregulated in acute myeloid Leukemia and 45. Chen C, et al. lncRNA-CCDC26, as a novel biomarker, predicts prognosis in appears to target the MiR-181 family. Cell Physiol Biochem. 2018;47(5):1998–2007. acute myeloid leukemia. Oncol Lett. 2019;18(3):2203–11. 72. Pan Y, et al. CircBA9.3 supports the survival of leukaemic cells by up- 46. Jia ZW, et al. Expression and clinical significance of LncRNA KCNQ1OT1 in regulating c-ABL1 or BCR-ABL1 protein levels. Blood Cells Mol Dis. 2018;73: patients with acute myeloid Leukemia. Zhongguo Shi Yan Xue Ye Xue Za 38–44. Zhi. 2018;26(3):653–7. 73. Xiao J, et al. SKP2 siRNA inhibits the degradation of P27kip1 and down- 47. Li S, et al. Identification of novel lncRNAs involved in the pathogenesis of regulates the expression of MRP in HL-60/a cells. Acta Biochim Biophys Sin childhood acute lymphoblastic leukemia. Oncol Lett. 2019;17(2):2081–90. Shanghai. 2009;41(8):699–708. 48. Shi J, et al. LncRNA LINP1 regulates acute myeloid leukemia progression via 74. Collins LJ, Penny D. The RNA infrastructure: dark matter of the eukaryotic HNF4alpha/AMPK/WNT5A signaling pathway. Hematol Oncol. 2019;37:474–82. cell? Trends Genet. 2009;25(3):120–8. 49. Peng L, Zhang Y, Xin H. lncRNA SNHG3 facilitates acute myeloid leukemia 75. Morris KV, Mattick JS. The rise of regulatory RNA. Nat Rev Genet. 2014;15: cell growth via the regulation of miR-758-3p/SRGN axis. J Cell Biochem. 423. 2019;121(2):1023-31. 76. Kung JTY, Colognori D, Lee JT. Long noncoding RNAs: past, present, and 50. de Souza Melo CP, et al. Long non-coding RNAs: biomarkers for acute future. Genetics. 2013;193(3):651–69. leukaemia subtypes. Br J Haematol. 2016;173(2):318–20. 77. Palazzo AF, Lee ES. Non-coding RNA: what is functional and what is junk? 51. Peng W, Feng J. Long noncoding RNA LUNAR1 associates with cell Front Genet. 2015;6:2. proliferation and predicts a poor prognosis in diffuse large B-cell 78. Iyer MK, et al. The landscape of long noncoding RNAs in the human lymphoma. Biomed Pharmacother. 2016;77:65–71. transcriptome. Nat Genet. 2015;47(3):199–208. 52. Zhang L, Xu H-G, Lu C. A novel long non-coding RNA T-ALL-R-LncR1 79. Bartonicek N, Maag JLV, Dinger ME. Long noncoding RNAs in cancer: knockdown and Par-4 cooperate to induce cellular apoptosis in T-cell acute mechanisms of action and technological advancements. Mol Cancer. 2016; lymphoblastic leukemia cells. Leuk Lymphoma. 2014;55(6):1373–82. 15(1):43. 53. Zhang X, Weissman SM, Newburger PE. Long intergenic non-coding RNA 80. Dhanoa JK, et al. Long non-coding RNA: its evolutionary relics and HOTAIRM1 regulates cell cycle progression during myeloid maturation in biological implications in mammals: a review. J Anim Sci Technol. 2018;60: NB4 human promyelocytic leukemia cells. RNA Biol. 2014;11(6):777–87. 25. 54. Díaz-Beyá M, et al. The lincRNA HOTAIRM1, located in the HOXA genomic 81. Prensner JR, Chinnaiyan AM. The emergence of lncRNAs in cancer biology. region, is expressed in acute myeloid leukemia, impacts prognosis in Cancer Discov. 2011;1(5):391–407. patients in the intermediate-risk cytogenetic category, and is associated 82. Wilusz JE, Sunwoo H, Spector DL. Long noncoding RNAs: functional with a distinctive microRNA signature. Oncotarget. 2015;6(31):31613–27. surprises from the RNA world. Genes Dev. 2009;23(13):1494–504. 55. Zeng C, et al. Overexpression of the long non-coding RNA PVT1 is 83. Li T, et al. Molecular mechanisms of long noncoding RNAs on gastric correlated with leukemic cell proliferation in acute promyelocytic leukemia. cancer. Oncotarget. 2016;7(8):8601–12. J Hematol Oncol. 2015;8:126. 84. Chen L, et al. Long Non-Coding RNA CCAT1 acts as a competing 56. Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and Cancer: a new endogenous RNA to regulate cell growth and differentiation in acute paradigm. Cancer Res. 2017;77(15):3965. myeloid Leukemia. Mol Cell. 2016;39(4):330–6. 57. Guo G, et al. A long noncoding RNA critically regulates Bcr-Abl-mediated 85. Merry CR, et al. DNMT1-associated long non-coding RNAs regulate global cellular transformation by acting as a competitive endogenous RNA. gene expression and DNA methylation in colon cancer. Hum Mol Genet. Oncogene. 2015;34(14):1768–79. 2015;24(21):6240–53. 58. Guarnerio J, et al. Oncogenic role of fusion-circRNAs derived from Cancer- 86. Lee RS, Roberts CWM. Linking the SWI/SNF complex to prostate cancer. Nat associated chromosomal translocations. Cell. 2016;165(2):289–302. Genet. 2013;45(11):1268–9. 59. LAbbate A, et al. MYC-containing amplicons in acute myeloid leukemia: 87. Arab K, et al. Long noncoding RNA TARID directs demethylation and activation genomic structures, evolution, and transcriptional consequences. Leukemia. of the tumor suppressor TCF21 via GADD45A. Mol Cell. 2014;55(4):604–14. 2018;32(10):2152–66. 88. Davidovich C, Cech TR. The recruitment of chromatin modifiers by long 60. Hirsch S, et al. Circular RNAs of the nucleophosmin (NPM1) gene in acute noncoding RNAs: lessons from PRC2. RNA. 2015;21(12):2007–22. myeloid leukemia. Haematologica. 2017;102(12):2039–47. 89. Wang KC, et al. A long noncoding RNA maintains active chromatin to 61. Li S, et al. Profiling and functional analysis of circular RNAs in acute coordinate homeotic gene expression. Nature. 2011;472(7341):120–4. promyelocytic leukemia and their dynamic regulation during all-trans 90. Lai F, et al. Activating RNAs associate with mediator to enhance chromatin retinoic acid treatment. Cell Death Dis. 2018;9(6):651. architecture and transcription. Nature. 2013;494(7438):497–501. 62. Wu D-M, et al. Role of circular RNA DLEU2 in human acute myeloid 91. Yang F, et al. The lncRNA firre anchors the inactive X chromosome to the Leukemia. Mol Cell Biol. 2018;38(20):e00259–18. nucleolus by binding CTCF and maintains H3K27me3 methylation. Genome 63. Li W, et al. Characterization of hsa_circ_0004277 as a new biomarker for Biol. 2015;16(1):52. acute myeloid Leukemia via circular RNA profile and bioinformatics analysis. 92. Schmitt AM, Chang HY. Long noncoding RNAs in Cancer pathways. Cancer Int J Mol Sci. 2017;18(3):597. Cell. 2016;29(4):452–63. 64. Xia L, et al. Circular RNA circ-CBFB promotes proliferation and inhibits 93. Pouyanrad S, Rahgozar S, Ghodousi ES. Dysregulation of miR-335-3p, targeted by apoptosis in chronic lymphocytic leukemia through regulating miR-607/ NEAT1 and MALAT1 long non-coding RNAs, is associated with poor prognosis in FZD3/Wnt/beta-catenin pathway. Biochem Biophys Res Commun. 2018; childhood acute lymphoblastic leukemia. Gene. 2019;692:35–43. 503(1):385–90. 94. El-Khazragy N, et al. The prognostic significance of the long non-coding 65. Wu W, et al. Downregulation of circ_0132266 in chronic lymphocytic RNAs "CCAT1, PVT1" in t (8;21) associated acute myeloid Leukemia. Gene. leukemia promoted cell viability through miR-337-3p/PML axis. Aging. 2019; 2019;707:172–7. 11(11):3561–73. 95. Tang P, et al. A 10-Long Non-Coding RNA-based expression signature as a 66. Shang J, et al. CircPAN3 mediates drug resistance in acute myeloid potential biomarker for prognosis of acute myeloid Leukemia. Med Sci leukemia through the miR-153-5p/miR-183-5p-XIAP axis. Exp Hematol. 2019; Monit. 2019;25:4999–5004. 70:42–54.e3. 96. Dong X, et al. Knockdown of Long noncoding RNA HOXA-AS2 suppresses 67. Shang J, et al. CircPAN3 contributes to drug resistance in acute myeloid Chemoresistance of acute myeloid Leukemia via the miR-520c-3p/S100A4 leukemia through regulation of autophagy. Leuk Res. 2019;85:106198. Axis. Cell Physiol Biochem. 2018;51(2):886–96. Bhat et al. Molecular Cancer (2020) 19:57 Page 19 of 21

97. Miller CR, et al. The long noncoding RNA, treRNA, decreases DNA damage 130. Wang W, et al. MicroRNA profiling of follicular lymphoma identifies and is associated with poor response to chemotherapy in chronic microRNAs related to cell proliferation and tumor response. Haematologica. lymphocytic leukemia. Oncotarget. 2017;8(16):25942–54. 2012;97(4):586–94. 98. Hughes JM, et al. C/EBPalpha-p30 protein induces expression of the 131. Jongen-Lavrencic M, et al. MicroRNA expression profiling in relation to the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia. genetic heterogeneity of acute myeloid leukemia. Blood. 2008;111(10):5078–85. Oncotarget. 2015;6(21):18534–44. 132. Lagos-Quintana M, et al. Identification of tissue-specific microRNAs from 99. Fang K, et al. A distinct set of long non-coding RNAs in childhood MLL- mouse. Curr Biol. 2002;12(9):735–9. rearranged acute lymphoblastic leukemia: biology and epigenetic target. 133. Fuster O, et al. Adverse prognostic value of MYBL2 overexpression and Hum Mol Genet. 2014;23(12):3278–88. association with microRNA-30 family in acute myeloid leukemia patients. 100. Conn SJ, et al. The RNA Binding Protein Quaking Regulates Formation of Leuk Res. 2013;37(12):1690–6. circRNAs. Cell. 2015;160(6):1125–34. 134. Yamamoto H, et al. miR-133 regulates Evi1 expression in AML cells as a 101. You X, et al. Neural circular RNAs are derived from synaptic genes and potential therapeutic target. Sci Rep. 2016;6:19204. regulated by development and plasticity. Nat Neurosci. 2015;18(4):603–10. 135. Xiao Y, Su C, Deng T. miR-223 decreases cell proliferation and enhances cell 102. Li X, et al. Long noncoding RNAs in head and neck cancer. Oncotarget. apoptosis in acute myeloid leukemia via targeting FBXW7. Oncol Lett. 2016; 2017;8(6):10726–40. 12(5):3531–6. 103. Perron MP, Provost P. Protein interactions and complexes in human 136. Pulikkan JA, et al. Cell-cycle regulator E2F1 and microRNA-223 comprise an microRNA biogenesis and function. Front Biosci. 2008;13:2537–47. autoregulatory negative feedback loop in acute myeloid leukemia. Blood. 104. Wightman B, Ha I, Ruvkun G. Posttranscriptional regulation of the 2010;115(9):1768–78. heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in 137. Lin X, et al. Serum MicroRNA-370 as a potential diagnostic and prognostic C. elegans. Cell. 1993;75(5):855–62. biomarker for pediatric acute myeloid leukemia. Int J Clin Exp Pathol. 2015; 105. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 8(11):14658–66. encodes small RNAs with antisense complementarity to lin-14. Cell. 1993; 138. Magee P, Shi L, Garofalo M. Role of microRNAs in chemoresistance. Ann 75(5):843–54. Transl Med. 2015;3(21):332. 106. Rajewsky N. L (ou) sy miRNA targets? Nat Struct Mol Biol. 2006;13(9):754–5. 139. Liu X, et al. miR-181a promotes G1/S transition and cell proliferation in 107. Rajewsky N. microRNA target predictions in animals. Nat Genet. 2006; pediatric acute myeloid leukemia by targeting ATM. J Cancer Res Clin 38(Suppl):S8–13. Oncol. 2016;142(1):77–87. 108. Liu W, Mao SY, Zhu WY. Impact of tiny miRNAs on cancers. World J 140. Hugo S, et al. Effect of miR-128 in DNA damage of HL-60 acute myeloid Gastroenterol. 2007;13(4):497–502. Leukemia cells. Curr Pharm Biotechnol. 2014;15(5):492–502. 109. Berezikov E, et al. Phylogenetic shadowing and computational identification 141. Volinia S, et al. A microRNA expression signature of human solid tumors of human microRNA genes. Cell. 2005;120(1):21–4. defines cancer gene targets. Proc Natl Acad Sci U S A. 2006;103(7):2257–61. 110. Stanczyk J, et al. Altered expression of MicroRNA in synovial fibroblasts and 142. Jiang X, et al. MicroRNA-221 sensitizes chronic myeloid leukemia cells to synovial tissue in rheumatoid arthritis. Arthritis Rheum. 2008;58(4):1001–9. imatinib by targeting STAT5. Leuk Lymphoma. 2019;60(7):1709–20. 111. Griffiths-Jones S. The microRNA registry. Nucleic Acids Res. 2004;32(Database 143. Jin J, et al. Decreased expression of microRNA-214 contributes to imatinib issue):D109–11. mesylate resistance of chronic myeloid leukemia patients by upregulating 112. Griffiths-Jones S, et al. miRBase: tools for microRNA genomics. Nucleic Acids ABCB1 gene expression. Exp Ther Med. 2018;16(3):1693–700. Res. 2008;36(Database issue):D154–8. 144. Rokah OH, et al. Downregulation of miR-31, miR-155, and miR-564 in 113. Cullen BR. Transcription and processing of human microRNA precursors. chronic myeloid leukemia cells. PLoS One. 2012;7(4):e35501. Mol Cell. 2004;16(6):861–5. 145. Li Y, et al. Inhibition of BCR/ABL protein expression by miR-203 sensitizes for 114. Esau C, et al. miR-122 regulation of lipid metabolism revealed by in vivo imatinib mesylate. PLoS One. 2013;8(4):e61858. antisense targeting. Cell Metab. 2006;3(2):87–98. 146. Salzman J, et al. Cell-type specific features of circular RNA expression. PLoS 115. Krutzfeldt J, et al. Silencing of microRNAs in vivo with 'antagomirs'. Nature. Genet. 2013;9(9):e1003777. 2005;438(7068):685–9. 147. Jeck WR, et al. Circular RNAs are abundant, conserved, and associated with 116. Zhao Y, Samal E, Srivastava D. Serum response factor regulates a muscle- ALU repeats. RNA. 2013;19(2):141–57. specific microRNA that targets Hand2 during cardiogenesis. Nature. 2005; 148. Memczak S, et al. Circular RNAs are a large class of animal RNAs with 436(7048):214–20. regulatory potency. Nature. 2013;495(7441):333–8. 117. Garzon R, et al. MicroRNA fingerprints during human megakaryocytopoiesis. 149. Danan M, et al. Transcriptome-wide discovery of circular RNAs in archaea. Proc Natl Acad Sci U S A. 2006;103(13):5078–83. Nucleic Acids Res. 2012;40(7):3131–42. 118. Monticelli S, et al. MicroRNA profiling of the murine hematopoietic system. 150. Wang PL, et al. Circular RNA is expressed across the eukaryotic tree of life. Genome Biol. 2005;6(8):R71. PLoS One. 2014;9(6):e90859. 119. Ambros V. The functions of animal microRNAs. Nature. 2004;431(7006):350–5. 151. Huang S, et al. The emerging role of circular RNAs in transcriptome 120. Lee YS, Dutta A. MicroRNAs: small but potent oncogenes or tumor regulation. Genomics. 2017;109(5):401–7. suppressors. Curr Opin Investig Drugs. 2006;7(6):560–4. 152. Ebbesen KK, Kjems J, Hansen TB. Circular RNAs: identification, biogenesis 121. Zhi Y, et al. Serum level of miR-10-5p as a prognostic biomarker for acute and function. Biochim Biophys Acta. 2016;1859(1):163–8. myeloid leukemia. Int J Hematol. 2015;102(3):296–303. 153. Chen L-L. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol 122. Zhao J, et al. Prognostic value of miR-96 in patients with acute myeloid Cell Biol. 2016;17(4):205–11. leukemia. Diagn Pathol. 2014;9:76. 154. Barrett SP, Salzman J. Circular RNAs: analysis, expression and potential 123. Shrestha S, et al. A systematic review of microRNA expression profiling functions. Development. 2016;143(11):1838. studies in human gastric cancer. Cancer Med. 2014;3(4):878–88. 155. Vicens Q, Westhof E. Biogenesis of circular RNAs. Cell. 2014;159(1):13–4. 124. Swartling FJ, et al. Deregulated proliferation and differentiation in brain 156. Hansen TB, et al. Natural RNA circles function as efficient microRNA tumors. Cell Tissue Res. 2015;359(1):225–54. sponges. Nature. 2013;495(7441):384–8. 125. Takahashi RU, Miyazaki H, Ochiya T. The roles of MicroRNAs in breast 157. Piwecka M, et al. Loss of a mammalian circular RNA locus causes miRNA Cancer. Cancers (Basel). 2015;7(2):598–616. deregulation and affects brain function. Science. 2017;357(6357):eaam8526. 126. Xu YM, et al. Regulation of miRNAs affects radiobiological response of lung 158. Tang W, et al. Silencing CDR1as inhibits colorectal cancer progression cancer stem cells. Biomed Res Int. 2015;2015:851841. through regulating microRNA-7. Onco Targets Ther. 2017;10:2045–56. 127. Nicolaidou V, Koufaris C. MicroRNA responses to environmental liver 159. Yu L, et al. The circular RNA Cdr1as act as an oncogene in hepatocellular carcinogens: Biological and clinical significance. Clin Chim Acta. 2015;445: carcinoma through targeting miR-7 expression. PLoS One. 2016;11(7): 25–33. e0158347. 128. Rodriguez-Montes JA, Menendez Sanchez P. Role of micro-RNA in colorectal 160. Guo JU, et al. Expanded identification and characterization of mammalian cancer screening. Cir Esp. 2014;92(10):654–8. circular RNAs. Genome Biol. 2014;15(7):409. 129. Bottoni A, Calin GA. MicroRNAs as main players in the pathogenesis of 161. Li J, et al. Circular RNAs in cancer: novel insights into origins, properties, chronic lymphocytic leukemia. Microrna. 2014;2(3):158–64. functions and implications. Am J Cancer Res. 2015;5(2):472–80. Bhat et al. Molecular Cancer (2020) 19:57 Page 20 of 21

162. Du WW, et al. Foxo3 circular RNA retards cell cycle progression via forming retinoic acid-induced differentiation/growth arrest. Leukemia. 2006;20(10): ternary complexes with p21 and CDK2. Nucleic Acids Res. 2016;44(6):2846–58. 1809–18. 163. Han D, et al. Circular RNA circMTO1 acts as the sponge of microRNA-9 to 191. Hermanson DL, et al. Overexpression of mcl-1 confers multidrug resistance, suppress hepatocellular carcinoma progression. Hepatology. 2017;66(4): whereas topoisomerase IIβ downregulation introduces mitoxantrone- 1151–64. specific drug resistance in acute myeloid leukemia. Mol Pharmacol. 2013; 164. Jeck WR, Sharpless NE. Detecting and characterizing circular RNAs. Nat 84(2):236–43. Biotechnol. 2014;32(5):453–61. 192. Heidenreich E, et al. Non-homologous end joining as an important 165. Hentze MW, Preiss T. Circular RNAs: splicing's enigma variations. EMBO J. mutagenic process in cell cycle-arrested cells. EMBO J. 2003;22(9):2274–83. 2013;32(7):923–5. 193. Hensel JP, et al. Breakpoints of t (4;11) translocations in the human MLL and 166. Yang Y, et al. Extensive translation of circular RNAs driven by N (6)- AF4 genes in ALL patients are preferentially clustered outside of high- methyladenosine. Cell Res. 2017;27(5):626–41. affinity matrix attachment regions. J Cell Biochem. 2001;82(2):299–309. 167. Pamudurti NR, et al. Translation of CircRNAs. Mol Cell. 2017;66(1):9–21.e7. 194. Domer P, et al. Molecular analysis of 13 cases of MLL/11q23 secondary 168. Wang Y, Wang Z. Efficient backsplicing produces translatable circular acute leukemia and identification of topoisomerase II consensus-binding mRNAs. RNA. 2015;21(2):172–9. sequences near the chromosomal breakpoint of a secondary leukemia with 169. Legnini I, et al. Circ-ZNF609 is a circular RNA that can be translated and the t (4;11). Leukemia. 1995;9:1305–12. functions in Myogenesis. Mol Cell. 2017;66(1):22–37.e9. 195. Chavali PL, Funa K, Chavali S. Cis-regulation of microRNA expression by 170. Memczak S, et al. Identification and characterization of circular RNAs as a scaffold/matrix-attachment regions. Nucleic Acids Res. 2011;39(16):6908–18. new class of putative biomarkers in human blood. PLoS One. 2015;10(10): 196. Lai T-H, et al. HDAC inhibition induces MicroRNA-182, which targets RAD51 e0141214. and impairs HR repair to sensitize cells to Sapacitabine in acute 171. Xia L, et al. Circular RNA circ-CBFB promotes proliferation and inhibits myelogenous Leukemia. Clin Cancer Res. 2016;22(14):3537–49. apoptosis in chronic lymphocytic leukemia through regulating miR-607/ 197. Garzon R, et al. Distinctive microRNA signature of acute myeloid leukemia FZD3/Wnt/β-catenin pathway. Biochem Biophys Res Commun. 2018;503(1): bearing cytoplasmic mutated nucleophosmin. Proc Natl Acad Sci U S A. 385–90. 2008;105(10):3945–50. 172. Ahmed I, et al. Altered expression pattern of circular RNAs in primary and 198. Zhang H, et al. Upregulation of microRNA-125b contributes to metastatic sites of epithelial ovarian carcinoma. Oncotarget. 2016;7(24): leukemogenesis and increases drug resistance in pediatric acute 36366–81. promyelocytic leukemia. Mol Cancer. 2011;10:108. 173. Ahmed I, et al. Identification of human genetic variants controlling circular 199. Kibria G, Hatakeyama H, Harashima H. Cancer multidrug resistance: RNA expression. RNA. 2019;25(12):1765–78. mechanisms involved and strategies for circumvention using a drug 174. Chang JE, Kahl BS. Bendamustine for treatment of chronic lymphocytic delivery system. Arch Pharm Res. 2014;37(1):4–15. leukemia. Expert Opin Pharmacother. 2012;13(10):1495–505. 200. de Oliveira JC, et al. Differential MiRNA expression in childhood acute 175. Foà R, et al. Chlorambucil plus rituximab with or without maintenance lymphoblastic leukemia and association with clinical and biological features. rituximab as first-line treatment for elderly chronic lymphocytic leukemia Leuk Res. 2012;36(3):293–8. patients. Am J Hematol. 2014;89(5):480–6. 201. Gefen N, et al. Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 176. Zenz T, et al. miR-34a as part of the resistance network in chronic (TEL/AML1) leukemias and confers survival advantage to growth inhibitory lymphocytic leukemia. Blood. 2009;113(16):3801–8. signals independent of p53. Leukemia. 2010;24(1):89–96. 177. Asslaber D, et al. microRNA-34a expression correlates with MDM2 SNP309 202. Schotte D, et al. MicroRNA characterize genetic diversity and drug polymorphism and treatment-free survival in chronic lymphocytic leukemia. resistance in pediatric acute lymphoblastic leukemia. Haematologica. 2011; Blood. 2010;115(21):4191–7. 96(5):703. 178. Zhu D-X, et al. miR-181a/b significantly enhances drug sensitivity in chronic 203. Wang H, et al. The effects of microRNAs on glucocorticoid responsiveness. J lymphocytic leukemia cells via targeting multiple anti-apoptosis genes. Cancer Res Clin Oncol. 2017;143(6):1005–11. Carcinogenesis. 2012;33(7):1294–301. 204. Yan J, et al. Deregulated MIR335 that targets MAPK1 is implicated in poor 179. Lu F, et al. miR-181b increases drug sensitivity in acute myeloid leukemia outcome of paediatric acute lymphoblastic leukaemia. Br J Haematol. 2013; via targeting HMGB1 and MCL-1. Int J Oncol. 2014;45:383–92. 163(1):93–103. 180. Zhou L, et al. microRNA-125b promotes leukemia cell resistance to 205. Mei Y, et al. Effect of microRNA-210 on prognosis and response to daunorubicin by inhibiting apoptosis. Mol Med Rep. 2014;9:1909–16. chemotherapeutic drugs in pediatric acute lymphoblastic leukemia. Cancer 181. Si W, et al. The role and mechanisms of action of microRNAs in cancer drug Sci. 2014;105(4):463–72. resistance. Clin Epigenetics. 2019;11(1):25. 206. Luo M, et al. Long non-coding RNAs control hematopoietic stem cell 182. Hershkovitz-Rokah O, et al. MiR-30e induces apoptosis and sensitizes K562 function. Cell Stem Cell. 2015;16(4):426–38. cells to imatinib treatment via regulation of the BCR–ABL protein. Cancer 207. Zhang X, et al. A myelopoiesis-associated regulatory intergenic noncoding Lett. 2015;356(2, Part B):597–605. RNA transcript within the human HOXA cluster. Blood. 2009;113(11):2526–34. 183. Wang L-S, et al. MicroRNA-486 regulates normal erythropoiesis and 208. Wei S, et al. PU.1 controls the expression of long noncoding RNA enhances growth and modulates drug response in CML progenitors. Blood. HOTAIRM1 during granulocytic differentiation. J Hematol Oncol. 2016;9(1):44. 2015;125(8):1302–13. 209. Wang H, et al. Transcription factors IRF8 and PU.1 are required for follicular 184. Löwenberg B, et al. High-dose Daunorubicin in older patients with acute B cell development and BCL6-driven germinal center responses. Proc Natl myeloid Leukemia. N Engl J Med. 2009;361(13):1235–48. Acad Sci U S A. 2019;116(19):9511–20. 185. Döhner H, et al. Diagnosis and management of acute myeloid leukemia in 210. Wang P, et al. The STAT3-binding long noncoding RNA lnc-DC controls adults: recommendations from an international expert panel, on behalf of human dendritic cell differentiation. Science (New York, NY). 2014;344(6181): the European LeukemiaNet. Blood. 2010;115(3):453–74. 310–3. 186. Estey E. AML in older patients: are we making progress? Best Pract Res Clin 211. Hirschberger S, Hinske LC, Kreth S. MiRNAs: dynamic regulators of immune Haematol. 2009;22(4):529–36. cell functions in inflammation and cancer. Cancer Lett. 2018;431:11–21. 187. D'Ugo E, et al. Identification of scaffold/matrix attachment region in 212. Schwarzer A, et al. The non-coding RNA landscape of human hematopoiesis recurrent site of woodchuck hepatitis virus integration. DNA Cell Biol. 1998; and leukemia. Nat Commun. 2017;8:218. https://doi.org/10.1038/s41467-017- 17(6):519–27. 00212-4. 188. Sumer H, et al. A rapid method of genomic array analysis of scaffold/matrix 213. Yildirim E, et al. Xist RNA is a potent suppressor of hematologic cancer in attachment regions (S/MARs) identifies a 2.5-Mb region of enhanced mice. Cell. 2013;152(4):727–42. scaffold/matrix attachment at a human neocentromere. Genome Res. 2003; 214. Léveillé N, et al. Genome-wide profiling of p53-regulated enhancer RNAs 13(7):1737–43. uncovers a subset of enhancers controlled by a lncRNA. Nat Commun. 189. Barone G, et al. Intercalation of Daunomycin into stacked DNA Base pairs. 2015;6:6520. DFT Study of an Anticancer Drug. J Biomol Struct Dyn. 2008;26:115–30. 215. Reisman D, et al. Evidence for a role of a lncRNA encoded from the p53 190. Chikamori K, et al. Downregulation of topoisomerase IIβ in myeloid tumor suppressor gene in maintaining the undifferentiated state of human leukemia cell lines leads to activation of apoptosis following all-trans myeloid leukemias. Gene Reports. 2016;5:45–50. Bhat et al. Molecular Cancer (2020) 19:57 Page 21 of 21

216. Blume CJ, et al. p53-dependent non-coding RNA networks in chronic 243. Zhao H, et al. HOX antisense lincRNA HOXA-AS2 is an apoptosis repressor in lymphocytic leukemia. Leukemia. 2015;29(10):2015–23. all trans retinoic acid treated NB4 promyelocytic leukemia cells. J Cell 217. Zeng C, et al. Inhibition of long non-coding RNA NEAT1 impairs myeloid Biochem. 2013;114(10):2375–83. differentiation in acute promyelocytic leukemia cells. BMC Cancer. 2014;14: 244. Isin M, et al. Investigation of circulating lncRNAs in B-cell neoplasms. Clin 693. Chim Acta. 2014;431:255–9. 218. Hayashi Y, et al. Antitumor immunity augments the therapeutic effects of 245. Xia T, et al. Long noncoding RNA FER1L4 suppresses cancer cell growth by p53 activation on acute myeloid leukemia. Nat Commun. 2019;10:4869. acting as a competing endogenous RNA and regulating PTEN expression. https://doi.org/10.1038/s41467-019-12555-1. Sci Rep. 2015;5:13445. 219. Brazão TF, et al. Long noncoding RNAs in B-cell development and 246. Chen P, et al. miR-9 is an essential oncogenic microRNA specifically activation. Blood. 2016;128(7):e10–9. overexpressed in mixed lineage leukemia-rearranged leukemia. Proc Natl 220. Liu Y, et al. Cloning of two candidate tumor suppressor genes within a 10 Acad Sci U S A. 2013;110(28):11511–6. kb region on chromosome 13q14, frequently deleted in chronic 247. Emmrich S, et al. miR-9 is a tumor suppressor in pediatric AML with t(8;21). lymphocytic leukemia. Oncogene. 1997;15(20):2463–73. Leukemia. 2014;28(5):1022–32. 221. Stilgenbauer S, et al. Expressed sequences as candidates for a novel tumor 248. Fu L, et al. A minicircuitry of microRNA-9-1 and RUNX1-RUNX1T1 suppressor gene at band 13q14 in B-cell chronic lymphocytic leukemia and contributes to leukemogenesis in t(8;21) acute myeloid leukemia. Int J mantle cell lymphoma. Oncogene. 1998;16(14):1891–7. Cancer. 2017;140(3):653–61. 222. Garding A, et al. Epigenetic upregulation of lncRNAs at 13q14.3 in leukemia 249. Bonizzato A, et al. CircRNAs in hematopoiesis and hematological is linked to the In Cis downregulation of a gene cluster that targets NF-kB. malignancies. Blood Cancer J. 2016;6(10):e483. PLoS Genet. 2013;9(4):e1003373. 250. Prendergast M, Schoenrock LD. Malar augmentation: patient classification 223. Mertens D, et al. Chronic lymphocytic leukemia and 13q14: miRs and more. and placement. Arch Otolaryngol Head Neck Surg. 1989;115(8):964–9. Leuk Lymphoma. 2009;50(3):502–5. 251. Guarnerio J, et al. Oncogenic role of fusion-circRNAs derived from Cancer- – 224. Herishanu Y, et al. The lymph node microenvironment promotes B-cell associated chromosomal translocations. Cell. 2016;166(4):1055 6. ğ receptor signaling, NF-kappaB activation, and tumor proliferation in chronic 252. Okcano lu TB, Gündüz C. Circular RNAs in leukemia. Biomed Reports. 2019; – lymphocytic leukemia. Blood. 2011;117(2):563–74. 0(0):1 5. 225. Krawczyk M, Emerson BM. p50-associated COX-2 extragenic RNA (PACER) activates COX-2 gene expression by occluding repressive NF-κB complexes. Publisher’sNote eLife. 2014;3:e01776. Springer Nature remains neutral with regard to jurisdictional claims in 226. Hu G, et al. LincRNA-Cox2 Promotes Late Inflammatory Gene Transcription published maps and institutional affiliations. in Macrophages through Modulating SWI/SNF-Mediated Chromatin Remodeling. J Immunol (Baltimore, Md : 1950). 2016;196(6):2799–808. 227. Hoesel B, Schmid JA. The complexity of NF-κB signaling in inflammation and cancer. Mol Cancer. 2013;12:86. 228. Trimarchi T, et al. Genome-wide mapping and characterization of notch- regulated long noncoding RNAs in acute leukemia. Cell. 2014;158(3):593–606. 229. Wang Y, et al. LncRNA NALT interaction with NOTCH1 promoted cell proliferation in pediatric T cell acute lymphoblastic leukemia. Sci Rep. 2015; 5:13749. https://doi.org/10.1038/srep13749. 230. Janghorban M, et al. Notch signaling as a regulator of the tumor immune response: to target or not to target? Front Immunol. 2018;9:1649. 231. Piro G, et al. Revising PTEN in the era of immunotherapy: new perspectives for an old story. Cancers. 2019;11(10):1525. 232. Guo G, et al. High expression of long non-coding RNA H19 is required for efficient tumorigenesis induced by Bcr-Abl oncogene. FEBS Lett. 2014; 588(9):1780–6. 233. Tseng Y-Y, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512(7512):82–6. 234. Casey SC, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352(6282):227. 235. Sun Y-M, et al. circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression. Blood. 2019; 134(18):1533–46. 236. Nicolet BP, et al. Circular RNA expression in human hematopoietic cells is widespread and cell-type specific. Nucleic Acids Res. 2018;46(16):8168–80. 237. Wu Y, et al. MicroRNA-17-92 controls T-cell responses in graft-versus-host disease and leukemia relapse in mice. Blood. 2015;126(11):1314–23. 238. Dakir E-H, Mollinedo F. Genome-wide miRNA profiling and pivotal roles of miRs 125a-5p and 17-92 cluster in human neutrophil maturation and differentiation of acute myeloid leukemia cells. Oncotarget. 2019;10(51): 5313–31. 239. Schneider E, et al. MicroRNA-708 is a novel regulator of the Hoxa9 program in myeloid cells. Leukemia. 2019. https://doi.org/10.1038/s41375-019-0651-1. 240. Wang X, et al. Noncoding RNAs and their functional involvement in regulation of chronic myeloid leukemia. Brief Funct Genomics. 2015;15(3): 239–48. 241. Yeh C-H, Moles R, Nicot C. Clinical significance of microRNAs in chronic and acute human leukemia. Mol Cancer. 2016;15(1):37. 242. Wang XQD, Dostie J. Reciprocal regulation of chromatin state and architecture by HOTAIRM1 contributes to temporal collinear HOXA gene activation. Nucleic Acids Res. 2017;45(3):1091–104.